Non-Medical Increase or Maintenance of Body Weight of a Mammal

ABSTRACT

Non-medical use of at least two components selected from the group of: (i) nucleoside equivalents, (ii) n-3 polyunsaturated fatty acids selected from the group of DHA, DPA and EPA, (iii) vitamins B, (iv) phospholipids, (v) antioxidants and (vi) cholines—with the proviso that at least one (i) nucleoside or at least one (iii) vitamin B is present—for increasing or maintaining the body weight, for improving the ability to perform an activity of daily living of a mammal, for maintaining the ability to perform an activity of daily living of a mammal, or for reducing a deterioration in the ability to perform an activity of daily living of a mammal.

FIELD OF THE INVENTION

The invention relates to a combination of specific components for use inincreasing or maintaining body weight. The invention also relates to anutritional composition that is particularly suitable for such use.

The invention also relates to the specific relevant benefits that can beachieved in such persons, like improvement of stamina, an increaseddegree of activity during daytime and associated change in lifestyle.

BACKGROUND OF THE INVENTION

Body weight of humans is determined by the weight of the different partsin the body, like that of bones, muscle, organs, vessels, adiposetissue, et cetera. During lifetime the contributions of each body partto the total body weight changes. After maturation of the human body hasstopped, typically muscle mass will gradually and steadily decrease withtime. This decrease results in a decrease of lean body mass (LBM, whichis the body mass minus the mass of adipose tissue), despite the factthat total body mass (or body weight) may increase, e.g. due to anincrease of the mass of adipose tissue and changed masses of other partsof the body. Ferruci et al. reported about the progression of loss ofmuscle strength during aging (Ferruci et al. (1996) J Gerontol Med Sci,51AM123-M130). The strength of a muscle is considered to be dependent onits mass. Its mass depends on the number of muscle fibres, whichdecreases only after 55 years of age to about 50% at the age of about 80years, their length, which depends on their trophic condition, and thecross-sectional area, which depends on training (Faulkner et al. (2007)Proc Au P S, 38; 69-75). Muscle strength (strength of handgrip orquadriceps) in normal persons appeared to decrease about 0.5% per yearafter the 30th year. Typically, this rate of decline of muscle strengthincreases with age. After the 65th year of age, this decrease in musclestrength has reached a magnitude of 1.5% per year for arm muscles andabout 3.5% for leg muscle (Skelton et al (1994) Age and Aging, 23,371-377). Similar age-associated changes in body composition and musclestrength have also been described by Evans, Cyr-Campbell (1997), JAmerican Dietetic Association, 97(6), 632, and by Campion (1998) N EnglJ med, 338(15), 1064-66.

It is important to note that, apart from these chronic age-associateddecreases in muscle mass and lean body weight, also temporal and mostlyreversible changes therein can occur, which in most cases depend on theapplied exercise efforts. For example, Muller observed that during longterm bed rest, muscle strength decreased at a rate of about 1% per day(Muller (1970) Arch Phys Med Rehabil, 51, 449-462).

These losses in body weight, lean body weight, muscle mass and musclestrength during aging are considered to be normal and physiological,though undesirable. It would be desirable to provide a way to slow downsuch effect of normal aging, or even reverse the loss.

It should be noted that in part of the human population these losseshave occurred at a greater speed or have occurred for a longer period oftime to reach a critical level. This abnormally large weight loss is inmost cases associated with several health problems which occur at thesame time. It is thought that a complex general and non-specificmalfunction of the human body causes a low capability of the human bodyto adapt to the prevalent circumstances to which the individual isexposed. This general condition is recognized by physicians as anindependent health problem for which the word sarcopenia was proposed.In the past, different tools have been used to arrive at the diagnosissarcopenia. Further, abnormal weight loss may result in health problems,in particular frailty (mild or moderate) or prefrailty.

Frailty is a large problem to the individual which experiences it, tothe environwent and to society. It has a large impact on theindividual's life and creates huge costs for medical care. For thisreason, the problem is recognized in the prior art as a geriatricsyndrome that is distinct from disability and comorbidity. In addition,a relatively low lean body mass and body weight in elderly andespecially in persons experiencing neurological problems, is common anda large problem, which has not yet been solved in the prior art.

Food intake, lifestyle and metabolic properties, including energyexpenditure, of an individual change with increasing age, which may leadto what has been called a “physiologic anorexia of aging”. Dietaryhabits, nutrient intake, life style and the aging process areinterrelated. For example, with decreasing activity during the appliedlife style, and the age-associated decline in basal metabolic rate,neuro-endocrine function, immune function and taste and smellperception, older people tend to consume less food, and consequentlyfewer nutrients, which may lead to a nutritional status, which does notthe specific requirements of the elderly of the frail individuals. Thiscomplex combination of events which is specific to aging individuals,can result in a further decrease in body weight, lean body mass or bodymass index (BMI). This may even result in frailty, as defined above.whereas, the use of specific components to reduce loss in body weight orincrease body weight in order to prophylactically or therapeuticallytreat frailty is generally considered as a medical treatment, thepresent disclosure is in particular directed at a non-medical use.Involuntary weight loss during aging above 65 years is stronglyassociated with impaired mood and low stamina.

In a specific embodiment of the invention, the specific combination ofcomponents according to the invention was found not only to increaseBMI, but also resulted in an improvement of the activities of dailyliving (ADL). Further it may improve the cognitive function. Thecomposition according to the invention may also have a beneficial effecton exhaustion or fatigue, as will be explained below.

The combination of low stamina, low drive to perform normal activitiesto keep independence and low abilities of skeletal muscles to allow theactivities of daily living may result in a low degree of activity duringdaily life, including the ability to purchase, prepare or consumeadequate food quality and quantity.

Therefore, there is a need to effectively improve the nutritional statusin mammals, ion particular humans, more in particular in elderly, havingan undersirably low body weight (low BMI in humans), in particular byincreasing lean body mass, healthy body weight, muscle capacity.Preferably, these effects are achieved in non-frail or prefrail persons,frail or prefrail elderly or elderly having a BMI below 23.5 kg/m². Morepreferably, these improvements in health result in a higher amount ofactivities during daytime, especially during wake time and in general abetter functioning in life and quality of life.

This specific improvement of the nutritional status of a subject is, inparticular a non-frail or prefail human having a relatively low bodyweight, is defined to be the nutritional management of the (nonfrail orprefrail) consumer. In the nutritional management of consumers, andespecially elderly it is also important to recognize the problem ofxerostomia or a dry mouth in general or during eating, and the problemof hypochlorhydria, i.e. the reduced secretion of hydrochloric acid bythe stomach, in general or after food intake or after smelling or seeingthe food. In one embodiment of the invention it is an objective toprovide a nutritional composition which, when consumed, is welltolerated and even appreciated by persons who suffer from xerostomia orhypochlorhydria.

It is known in the prior art that supplementation of protein and energyto elderly who are at risk from malnutrition produces a small butconsistent weight gain (Milne et al. (2009) Cochrane review). Healthypersons like athletes can increase their BMI, when very high amounts ofspecific proteins, peptides or amino acids are consumed, in particularwhen this is combined with an exercise protocol. The known approach tosupplement additional protein and energy demands consumption of food ontop of daily meals, and a proper organ function, for dealing with thelarge amount of dietetic protein (i.e. nitrogen). in particular, theelderly, may experience difficulties with consuming large quantities orvolumes of food, may suffer from impairments in body and organ functionor from early satiety and low appetite, have practical problems withcooking and with consuming the food products, and are not keen on orcapable of applying exercise programs (Holmes (2008) Nursing standard,22 (26), 47-57).

Accordingly, there is a need for an alternative way of nutritionalmanagement of elderly which are in need of an increased body weight,body mass index, lean body weight, muscle mass or muscle strength, toperform appropriately, especially elderly

Preferably, the composition according the invention achieves allbenefits as described above at about the same time. This is observed inelderly in general (above 65 years of age), but also in a subgroupthereof, the oldest one (persons above 75 years of age). In a preferredembodiment, the nutritional composition according to the invention is tobe used for treating increasing low body weight or BMI and for improvingactivities of daily living (ADL), especially in persons older than 50years of age, more in particular those older than 65 years of age(elderly) and in particular older than 75 years of age (the oldest). Thecomposition according to the invention may also be used to combat otherundesirable effectsy, such as exhaustion or fatigue by its effect onmuscle power, and thrive or stamina and the effect on neurologicalperformance, in particular cognition.

BACKGROUND PRIOR ART

In WO2009/002146 (NV Nutricia), a composition is disclosed whichcomprises DHA or EPA, in combination with uridine or its equivalent andoptionally a range of other components to support activities of dailyliving. The composition can be administered to elderly and locomotorfunction appeared improved by administering these components. Also,protein could be included in the composition of the invention, in orderto improve muscle strength, when administered to frail elderly. In orderto achieve this, in particular 1 to 5 g protein per 100 ml of a liquidcomposition was included, wherein the protein comprises more than 80weight % milk-derived proteins.

WO2010/002257 (NV Nutricia) discloses the use of a nutritionalpreparation comprising more than 18 energy percent protein (preferably22 to 32 en %), whey protein, at least 12 g leucine per 100 gproteinaceous matter and a lipid fraction which comprises at least oneof EPA, (n-3)DPA, DHA and (n-3) ETA for improving muscle function in amammal. The improvement of the function of muscle was in terms ofmaximum force, maximum contraction velocity and maximum relaxationvelocity, all corrected for muscle mass. This improvement was claimed tooccur when the mammal suffered from specific diseases, in particularcancer or during “aging” and was claimed to result in improving dailyactivity, physical performance and quality of life. Frail individuals assuch were not mentioned and neither were elderly with a low BMI orelderly being frail. The composition as disclosed comprises preferablythe components as mentioned and in addition specific indigestibleoligosaccharides, glutamine, cysteine, oligosaccharides, carnitine andtaurine. Though soy protein and wheat protein were mentioned theinclusion of casein instead of these vegetable proteins was preferred.Nucleotides and uridine sources were not mentioned.

WO 2005/060952 (NV Nutricia) relates to a composition comprising in adaily dosage form 14 to 1000 mg panthothenic acid (vitamin B5) forstimulating appetite, whereby body weight and muscle mass is increasedin specific groups of diseased humans. This was surprising, sincepanthothenic acid had been reported before as a hunger suppressant. Thecomposition may further comprise folic acid, vitamin C (as antioxidant),and vitamin B6 and B12 as part of a common vitamin premix.

WO2007/073178 (NV Nutricia) discloses a drink liquid for Alzheimerpatients (Example 3) comprising a nucleoside equivalent (UMP), fish oilcomprising DHA and EPA, vitamin B6, folic acid and vitamin B12,phospholipids, vitamin C (as antioxidant), and choline. The claimedeffect is not disclosed.

WO2004/026294 (Nestec S.A.) discloses a nutritional composition whichcomprises leucine and at least one of isoleucine, lysine, methionine,phenylalanine, threonine, tryptophan, valine or histidine in free orsalt form, wherein free leucine is present in an amount of 10 to 35weight % of the total amount of amino acids. Such composition wasclaimed to be useful for controlling tumour-induced weight loss, forstimulating protein synthesis, ameliorating loss of muscle in a human orfor the dietary management of malnutrition.

SUMMARY DESCRIPTION OF THE INVENTION

It has now been found that lean body mass (LBW) or the body mass index(BMI) can be increased in mammals, o by providing a nutritional orpharmaceutical composition comprising a specific combination of activecomponents. Further, it has been found that LBW or BMI can be increasedfor non-medical purposes.

Accordingly, the invention relates to the non-medical use of acomposition comprising at least two, preferably three, and morepreferably four components (as active ingredients) selected from thegroup of (i) nucleoside equivalents, (ii) n-3 polyunsaturated fattyacids selected from the group of DHA, DPA and EPA, (iii) vitamins Bselected from the group of vitamin B6, vitamin B9 and vitamin B12, (iv)a phospholipid, (v) an antioxidant selected from the group of vitamin C,vitamin E and selenium (including selenium compounds), and (vi)cholines—with the proviso that at least one (i) nucleoside or at leastone of said (iii) vitamins B is present for increasing or maintainingthe body weight of a mammal. This can be accomplished by administeringthe components used according to the invention, wherein the componentsare administered to the mammal in a diet without essentially increasingthe daily caloric intake of the mammal. The combination is used forincreasing or maintaining the body weight for a non-medical reason. Suchreason may in particular be cosmetic, such as to improve physicalappearance, especially of elderly people, or the use may contribute toimproving quality of life for other than for medical reason. E.g. normalaging effects may be slowed down, or it may contribute to lettingelderly live independently until a later age. In particular, elderlywith an age above 65 years of age, preferably with an age may benefitfrom a use according to the invention.

Further, the invention relates to the non-medical use of at least twocomponents selected from the group of: (i) nucleoside equivalents, (ii)n-3 polyunsaturated fatty acids selected from the group of DHA, DPA andEPA, (iii) vitamins B selected from the group of vitamin B6, vitamin B9and vitamin B12, (iv) a phospholipid, (v) an antioxidant selected fromthe group of vitamin C, vitamin E and selenium (including seleniumcompounds), and (vi) cholines—with the proviso that at least one (i)nucleoside or at least one of said (iii) vitamins B is present—are usedin a non-medical or medical method for improving the ability to performan activity of daily living of a mammal, for maintaining the ability toperform an activity of daily living (ADL) of a mammal, or for reducing adeterioration in the ability to perform an activity of daily living of amammal.

When referred herein after to a ‘vitamin B’, in general a vitamin Bselected from the group of folates, pyridoxins and cobalamines is meant,unless specifically stated otherwise. When referred herein after to an‘antioxidant’, in general an antioxidant selected from the group ofvitamin C (ascorbates), vitamin E (tocopherols) and selenium (includingselenium compounds) (v) is meant, unless specifically stated otherwise.

When referring to an acid (e.g. ascorbic acid or folic acid), itsconjugated anion, e.g. ascorbate respectively folate, is meant to beincluded, unless specifically stated otherwise. Likewise, when referringto a base (e.g. folate, ascorbate), its conjugated acid (e.g. folicacid, respectively ascorbic acid) is meant to be included unlessspecifically stated otherwise.

Further, the invention relates to a nutritional composition comprising(i) at least two components selected from the group of uridine anduridine monophosphate, (ii) DHA and EPA, (iii) a vitamin B, (iv) aphospholipid, v) an antioxidant, and (vi) a choline.

Such composition is in particular suitable for a use according to theinvention.

The term ‘active ingredient’ or ‘active component’ is used herein inparticular for (i) nucleoside equivalents, (ii) n-3 polyunsaturatedfatty acids selected from the group of DHA, DPA and EPA, (iii) vitaminsB, (iv) phospholipids, (v) antioxidants and (vi) cholines, which areeffective in one or more of the claimed uses. They may be present in acombination or composition (for use) according to the invention in anyphysiologically acceptable form.

If a specific compound falls in more than one of these groups (i)-(vi)of active ingredients it typically provides an active ingredient of bothgroups. The actual dosage or concentration provided for each group canbe determined based on how the compound is used/metabolised afteradministration. For example, phosphatidyl choline (PC) is both aphospholipid and a choline. As a phospholipid it can be active in thedistrubution/emulsification of lipids, and thereafter it can bemetabolised to release the choline, which is an essential component formammals, such as humans. Thus, a composition comprising PC comprisesboth an active ingredient of the group of phospholipids and of the groupof cholines. Another example of a compound providing more than one typeof active ingredients is Citicoline (cytidine diphosphate-choline),which provides both choline and a nucleoside source.

In an advantageous embodiment, a nutritional the use of a compositionused according the invention results in a further improvement in theamount of activities of daily living that can be performed and anincreased muscle mass, muscle strength or muscle function, when also aspecific protein amount is included in the composition according to theinvention. In particular, the composition according the invention may beused to improve stamina, to increase degree and frequency of feelingmore energetic, to decrease duration, severity or frequency of feelingtired or exhausted or feeling fatigue, or to increase eagerness todemonstrate initiatives and become more active. In addition thecomposition according the invention can improve gait.

It has also been found that mammals physically benefit from treatmentwith a specific combination of active ingredients such that one or moreof body weight, body mass index, or lean body weight are bettermaintained or even increased without the need to increase the dailycaloric intake of said mammals.

The components as described above can be combined with a specificprotein composition to obtain a stronger effect on LBM or BMI.

The term “or”, as used herein, means also “and”, unless specifiedotherwise or the context dictates otherwise. Hence, “option A or B”means any of the options A, B and A and B.

The term “a” or “an”, as used herein, means “at least one” unlessspecified otherwise.

When referring to a noun (e.g. a compound, an additive etc.) insingular, the plural is meant to be included, unless specifiedotherwise.

When referring herein to an acid, e.g. a fatty acid or folic acid, thisterm is meant to include the conjugated bases of said acid (e.g.folate), salts of the acids and derivatives of the acid of which thebody is capable of converting it into the acid (e.g. fatty acid esters,such as triglycerides), unless specified otherwise.

When referring herein to dosages, these are in particular intended foradult humans. The skilled person will be able to determine a suitabledosage for other mammals based on common general knowledge, theinformation disclosed herein and optionally a limited amount of routinetesting.

When referring to a mammal, preferably the mammal is a human mammal,more preferably an elderly human mammal.

DETAILED DESCRIPTION OF THE INVENTION Definition of Frailty

For the purpose of this document, the inventors apply the followingdefinition for frailty, which includes the practical approaches of manyscientists (like Fried, Ory, and Chin A Paw). A person is deemed to befrail when the individual's condition in a recent period of timecomplies with at least 3 of the following list of (6) classes ofsymptoms (frailty criterions):

1. Muscle weakness,

2. Excessive feelings of exhaustion or fatigue,

3. Abnormally low physical activity,

4. Slow or unsteady gait,

5. Weight loss, and

6. Neurological dysfunction

The degree of malfunction of each of the mentioned classes of symptomscan be measured by applying recognized methods that are known in theprior art. For the purpose of this invention, the application of thefollowing methods is preferred:

Criterion 1 (Muscle Weakness)

For determining muscle weakness one of the following list: a) formuscles of the arm: hand grip strength or quadriceps strength, b) forthe leg the method as described by BØrsheim et al. (2008) Clin Nutr. 27,189-195; or as described in Pijnappels et al. (2008) Eur J Appl Physiol.102(5): 585-592 can be applied. Belonging to the lower 20% of the groupof age and gender matched persons resulted in fulfilment of this frailtycriterion.

Criterion 2 (Feeling of Exhaustion or Fatigue)

For determining the degree of exhaustion or fatigue, one can assess oneor more of a) mental fatigue, b) the perception of exerting astandardized exercise protocol, muscle capacity or muscle power, or c)lung capacity. Preferably, method a) is done by applying a questionnaireas known in the prior art, e.g. the CES-D scale as described by Roberts(1980) Psychiatr Res, 2, 125-134, so scoring on statements like “Icannot get going” or “I feel that everything I do is an effort”. Thismeasure is strongly related to the degree of stamina of the individual.Method b) is a measure of physical exhaustion and can for example bedone by applying the Borg scale for measuring perceived exertion (Borg(1998) Human kinetics, Champaign, Ill.; Nybo (2003) Med Sci SportsExerc, 35, 589-594). Method c) is a measure of the capacity of a humanbeing to provide sufficient oxygen (air) to the body. The preferredmethod for applying it, is measuring forced expiratory volume (FEV1) inone second, which should be below 30% of the normal value, forindividuals of similar age and gender, in order to meet the criterion.

Measurement of the degree of physical exhaustion or fatigue, asrecommended in method b) can be done in several ways, which allrepresent ways that reflect the capacity of the neuro-muscular system toexert labour and be active. For example, the amount of physicalactivities can be measured, by attachment of devices to the person to betested, and measuring the amount of physical activity which isvoluntarily applied normally during wake time. This amount can also berelated to the amount of sleep or rest that is needed to recover fromit, and be put in a score. Secondly, the capacity of the muscle tomaintain a certain force for a certain time is a useful measure.Preferably, this force that needs to be maintained is at 15 to 80% ofthe maximal force the muscle can provide, in order to reflect better theactivities as applied in normal life. Thirdly, the speed with whichphysical exhaustion is developed can be determined. For example, theamount of power a muscle can exert in a certain period of time can bedetermined; e.g. by measuring the force multiplied with the distance (ina movement) that the force was exerted, e.g. by swinging a leg at acertain velocity. Equipment for measuring these advanced parameters iscommercially available. The speed with which a muscle can become tired,or in other words, the time that a certain force can be maintained, is avaluable measure of the capability of an organism to apply dailyactivities. When the measured values for these parameters in the testedperson belong to the lower 20% of such values for a group of persons ofsimilar age and gender, the person is deemed to comply with thiscriterion of frailty.

It is important to recognise that larger muscle strength does not in allcircumstances necessarily lead to a higher muscle capacity or power or abetter endurance. The larger force which is provided by the muscle mayhave exhausted endogenous energy supplies more, which deteriorates thetime or distance that the muscle can exert the force, and therefore doesnot increase muscle capacity or power. A larger force may also increasenegative feedback signals from peripheral joints, muscles and tendons.Muscle capacity or muscle power also better reflects the muscle effortthat needs to be done to apply an activity of daily living (Theou et al.(2008) Appl Physiol, Katsiaris, et al, 2005). Therefore, muscle capacityor muscle power, and not muscle strength, provides useful informationabout the state of exhaustion and fatigue, and especially physicalexhaustion and fatigue of a subject. The force that a skeletal musclecan apply also influences the maximal velocity with which a certainmovement can be made. A high movement velocity does not automaticallyresult in a large endurance or a good recovery after exercise, which arerequired for performing a large amount of activities or showing a highmobility during wake time over the day.

Criterion 3 (Physical Activity)

For determining the magnitude of physical activity of a human, one ormore methods of the following list can be applied: a) determination ofthe amount of basic activities as applied during daily life (asdescribed above), and b) determination of the amount of instrumentalactivities, as applied during daily life. Especially the measurement ofinstrumental activities is a valuable measure. A reliable method to dothis is assessment of the “Physical Activity Scale for the Elderly”(PASE), as described by Washburn et al. (1999) J Clin Epidemiol 52,643-651; “The physical activity scale for the elderly; evidence forvalidity”. For men, a score of less than 30 and belonging to lowest 20%part fulfilled this criterion for frailty. For women, the thresholdvalue was <27.5 (Graham et al. (2009) Gerontol, 55, 644-651).

Criterion 4 (Gait)

For determining the gait of a human, tests can be applied, like thosedescribed in the “Modified Physical Performance Test” (PTT), asdisclosed by Binder et al. (1999) J Gerontol, 54, M428-432, like thepreferred a) measure of “balance”, as e.g. done by determining the wayhow a frail person is capable of taking a penny from the floor, or b)time and way to walk 5 to 15 meters, or c) time and way to raise from achair. For example, for method b) the criterion for frailty wasfulfilled when the person belonged to 20% of persons with regard to thetime needed. The threshold values per gender as mentioned in Graham etal. (2009) Gerontol, 55, 644-651 can suitably be applied.

Criterion 5 (Weight Loss)

For determining the presence of undesired weight loss, it is importantto avoid confusion with acute weight loss as caused by a (serious)disease or trauma or an underlying pre-death syndrome. In one embodimentof the invention, frailty as the result of cachexia is excluded from thegroup of persons wherein the composition according to the invention iseffective. In one embodiment of the invention, this exclusion of personswho have become frail because of cachexia is preferred. In this way,frail individuals which comply with the definition as given above differfrom the individuals which have developed a frailty that results fromthese diagnosed conditions, related to acute phases during diseases andbriefly before death.

With regard to determining the value of BMI, which should give concernsfor becoming “frail”, it is important to be aware of the fact thatoptimal BMI values change with age. While at young and middle age a BMIvalue between 20 to 25 kg per square meter is considered to be mosthealthy, at older age, e.g. above 65 years of age and especially above75 years of age, a BMI below 23.5 is considered to be undesirable (ChinA Paw et al. (2003) J Nutr Health Aging 7(1), 55-60, or Chin (1999) JClin Epidemiol 52 (11), 1015-1021). The preferred list of diagnostictools for establishing a too low body weight, lean body mass or musclemass aims to be suitable for the aged population.

For the purpose of the invention, the inventors feel that it isdesirable to look carefully at the metabolic condition of the individualwho suffers from a low BMI, body weight or muscle capacity. When suchlow body weight is the result of an acute process, the metaboliccondition of the individual differs on essential points from that of aperson who experiences a more generalized metabolic problem. Thisdifference has also been made by others, for example for Alzheimerpatients (Guerin et al. (2005) Am J Clin Nutr, 82 (2), 435-441). Part ofthe Alzheimer patients appear to experience sudden and severe weightloss as a result of intercurrent events, like institutionalization, amajor change in life style, a trauma or the presence of a major disease,while a different part suffered from a more chronic weight loss.Therefore it is preferred that the BMI value, as proposed as a limit formeeting one criterion of frailty, is assessed in the absence of an acutephase condition, i.e. the absence of a diagnosed disease selected from acancer, AIDS, a COPD, an infection, pre-death, pre-death associated withanorexia, surgery, an accident and similar major trauma, or in analternative embodiment the acute phases during these diseases orconditions. The presence of the acute phase during these diseases can bedetermined by measuring a biomarker as known in the prior art, e.g.measuring plasma concentrations of acute phase proteins, liketranthyretin, alpha1-acid glycoprotein, C-reactive protein, or measuringconcentrations of cytokines which are representative of acute infectionsor severely progressed disease, like IL-1, IL-6 or TNF-α. It isimportant to note that a disease, like cancer, chronic obstructivepulmonary diseases, AIDS and other diseases or pre-death, at some stagecan cause a frailty condition that is acute and severe. The inventorsfind that the metabolic condition of such individual is completelydifferent from that of an individual suffering from a frailty thatorigins from a generalized metabolic inability to cope with the dailystresses from the outside world. Therefore, in the context of thisinvention, frailty, which is treated and solved by administering thenutritional or pharmaceutical composition according the invention, isnot this acute-, and disease- or trauma-related type of advanced weightloss or frailty. Instead, it is the frailty as defined below and causedby a general and complex deterioration of the body to adapt the externalstresses, as can have been acquired during life e.g., by applying badlife style including bad dietary habits, exposure to toxicants or as aresult of time, as occurs during aging, in particular by aging after 65years of age and more in particular the frailty as caused by a chronicdeterioration of adaptive responses.

Further, a method for determining involuntary weight loss can be usedfor assessing whether criterion 5 applies, applying the criterion of 4.5kg undesired weight loss in the previous year, or 5-10% of body weightwithin 6-12 months or less. Involuntary weight loss of a subject isweight loss occurring despite the subject's aim to maintain or increaseits bodyweight (on the subject's own behalf or after advice of career orhealth care professional). Such weight loss can be determined routinelyby comparing present weight at with the weight in a period 1-2 yearsearlier and asking the subject whether he aimed to maintain or increasehis body weight.

Further, a method can be used applying the criterion of 6 kg undesiredor unexplainable weight loss during previous 2 years. Such weight losscan be determined routinely by comparing present weight at with theweight in a period 2 years earlier and asking the subject whether heaimed to maintain or increase his body weight and whether he is aware ofany other reasons that might explain a weight loss, A pre-deathcondition can be diagnosed by a physician. Measurement of transthyretinand α1-acid glycoprotein in blood plasma of both genders and thedetermination of low blood albumin and high C-reactive protein in bloodof males, as applied by Carriere (POLA Group) et al. (1998) ArchOphthalmology, 116, 1031) is recommended for establishing predeath risk.

Criterion 6 (Neurological Dysfunction)

For determining the degree of neurological dysfunction application ofthe following list is preferred: a) establishment of a tremor or alocomotor dysfunction different from the balance and performance testsapplied in measuring gait performance; b) measurement of cognitivefunction (impairwent); c) determionation of verbal fluency; d)measurement of speed of conductance of electrical signals over nerves;e) analyses of sensory functioning, to establish a problem related tohearing, vision, tasting, smelling and touch); f) measurement of aemotional or psychological condition, like establishing the presence ofmajor depression, an affect disorder or an anxiety disorder; g)determination of incontinence or the daily occurrence of significantinvoluntary urinary loss, and h) the presence of a major sleep disorder,like chronic insomnia or sleep apnea. Methods to assess neurologicaldysfunction have been described in the prior art and include the DSM IVmethods, and the measurements as described in the corresponding domainsin common frailty assessment methods, like the Groningen frailtyindicator (Schuurmans et al. (2004) J Gerontol, Biol Sci, Med Sci, 59,M962-5), the comprehensive geriatric assessment (FI-SGA: Goggins et al.(2005) 60, 1046; Jones et al. (2004) J Am Geriatr Soc, 52, 1929-33) orthe clinical global impression of change in physical frailty (CGIC-PF:Studenski et al. (2004) J AM Geriatr Soc, 52, 1560-6). Involuntary urineloss is deemed to be significant when it exceeds 10 ml a day.

A subject is considered to meet this neurological dysfunction criterionof frailty when b) is met (cognitive impairment) or, when a combinationof at least two of the other criterions has been fulfilled. Cognitiveimpairment can be assessed by methods known in the prior art, forexample by applying measures of the domains related to the measurementof verbal memory, visuospatial memory and attention-executive abilities.Preferred methods include application of the ADAS-cog assessment, theMMSE assessment, the Montreal cognition assessment or the CERAD methods.

The analyses of sensory function can be applied by using methods knownin the prior art to determine threshold values for tastes, odours andsounds, or to determine the ability to differentiate between differentodours and tastes.

A person is considered to be mildly frail when it complies with three ofthe six criterions, and moderately frail when it complies with fourcriterions or when the score of the three symptoms is so bad, that itseriously impairs the person's condition, as diagnosed by the clinicianor physician.

A person is considered to be in nonfrail if none or only one of the sixfrailty conditions are complied with.

A person is considered to be in a prefrail condition or prodromal frailcondition, when his or her condition complies with only two of the sixfrailty criterions. When the composition according to the inventiontreats prefrailty, it is defined to act in a preventive manner on thedevelopment of frailty. So, prefrailty and prodromal frailty is definedto be synonymous.

A person is defined to be a frail elderly when it complies with theabove-mentioned criterions for frailty and in addition is older than 65,preferably 75 years of age.

An individual is defined to be a prefrail elderly when the person'scondition complies with the criterions of prefrailty and the person isolder than 65, preferably 75 years of age.

Within the context of this invention, when the term “frailty” is used tocomprise conditions indicated above as prefrail, prodromal frail, mildlyfrail or moderately frail.

Though some scientists recognize various forms of frailty, includingmedical, functional, social, psychological and physical frailty (Faberet al. (2006) Arch Phys Med Rehabil. 87, 885-96), the compositionaccording the invention aims to have its efficacy only in those subjectswhich comply exactly with the criterions as set above.

Elderly or the aged population is a group that is defined in differentways in the prior art. For the purpose of defining the invention, theinventors have applied the following definition. Elderly or the agedpopulation is defined to be all persons being older than 65 years ofage. The “oldest old” are those persons being older than 75 years. Theclaimed combination for use in accordance with the invention is inparticular suitable for treatment of a mammal. In a preferredembodiment, said combination is to be used for the treatment of a human,in particular an elderly person. In the context of this application, anelderly person is a person of the age of 50 or more, in particular ofthe age of 55 or more, more in particular of the age of 60 or more, morein particular of the age of 65 or more. This rather broad definitiontakes into account the fact that the average age varies betweendifferent populations, on different continents, etc. Most developedworld countries have accepted the chronological age of 65 years as adefinition of ‘elderly’ or older person (associated with the age atwhich one may begin to receive pension benefits), but like manywesternized concepts, this does not adapt well to e.g. the situation inAfrica. At the moment, there is no United Nations (UN) standardnumerical criterion, but the UN agreed cut-off is 60+ years to refer tothe older population in Western world. The more traditional Africandefinitions of an elder or ‘elderly’ person correlate with thechronological ages of 50 to 65 years, depending on the setting, theregion and the country.

With the “nutritional management of frail individuals, prefrailindividuals and persons experiencing a too low LBM or BMI” according theinvention is meant the administration of nutritional components to frailindividuals, prefrail individuals or persons having a too low BMI orLBM, in such a way that not only the endogenous concentrations ofnutritional components are influenced, but that also thehealth-beneficial effect is obtained in persons suffering from frailty,frailty symptoms, prefrail persons or individuals suffering from a toolow LBM or BMI as claimed in this application. This means that thecomposition according the invention may induce a concentration in bloodof that nutrient, which is outside the normal range as typicallyobserved in the same tissue of healthy individuals, for example ofhealthy individuals which consume regular food or a normal diet. In thecontext of this invention, an alternative way of saying the same is thatthe composition according to the invention also aims to therapeuticallynourish frail or prefrail persons or persons having too low LBM or BMI.

It is important to notice that many elderly have become malnourished andhave developed deficiencies in one or more nutrients like protein,energy or microingredients or combinations thereof, like PEM(protein-energy malnourishment). Such “malnourishment” is currentlyassessed by using tools like the “MUST” or “MNA”, but it is envisaged bythe inventors that alternative tools will be developed, like one that isspecifically focussing on nourishment status and one other tool whichspecifically focuses on general and quick screening of the condition ofan individual in order to assess whether a condition is present whereinadditional nutrition or other therapy can be useful. Therefore, in oneembodiment of the invention the composition according to the inventionis used in combination with an assessment of malnourishment of a mammal,preferably using MUST or MNA. In this embodiment, the inventioncomprises at least the following steps:

-   -   1—Assessment of the nutritional status of a mammal, and    -   2—Intervention with the nutritional or pharmaceutical        composition according the invention.

Preferably, the assessment of nutritional status is applied at leasttwice in combination and relation to the nutritional intervention. Morepreferably, the assessment is done at least one time before and at leastone time after the intervention to measure any changes in nutritionalstatus. The initial nutritional assessment may reveal deficiencies whichcan be resolved by adapting the intervention composition according tothe invention. In order to allow such nutritional management accordingthe invention, separate tools have been defined which is a specificnutritional assessment tool and a module of food components which allowsconvenient adapatation and fortification of the nutritional interventioncomposition according to the invention.

A preferred tool for assessing nutritional status comprises severalparts, including a questionnaire, which asks the right questions toassess nutritional status, a database which is filled in by answeringthe questions, and an algorithm which compares the answers withpredefined normal values. Optionally conclusions are drawn to arrive atan advice. These functionalities can be incorporated into an electronicdevice like a computer or minicomputer, by loading and running anappropriate software program. The questions to ask are at least coveringbiomarkers for the determination of nutrient status using methods asapplied in the state of the prior art clinical chemistry laboratories.

Apart from the “nutritional management”, the inventors also identify the“therapeutic management” of frailty and prefrailty. In this definitionof “therapeutic management”, the management of the individual to betreated comprises at least the following steps:

a) diagnosis for frailty, using an assessment of the six criterionsdefined above for assessing the presence of frailty,

b) an intervention using the composition according the invention, and

c) measurement of progress made by assessing at least again the samesymptom classes as done in step a).

Preferably, the assessment of symptoms is done by using the tool, inparticular a form or document or an electronic device loaded withappropriate software, as described below.

Optionally, in the management of frailty and prefrailty, theintervention with the nutritional composition according to the inventioncan be combined with one or more of 1) an exercise program, 2) a programto improve social interactions, 3) a program to become more exposed tosunlight and fresh air, 4) an adaptation of the diet or of the generalfood intake practices of the subject, and 5) an intervention with a drugor medicine. It is preferred that the therapeutic management comprisesat least a program to be exposed to sunlight and fresh air or anexercise program as a fourth and fifth step in the therapeuticmanagement of the condition of the subject.

In principle, the mammal to be treated may suffer from any of thefrailty symptoms as defined above. In particular, the mammal is a humanwhich suffer from at least a neurological or brain problem and oneselected from the group of weight loss and an abnormally low physicalactivity. Preferably, the subject is non-frail or frail. Preferably, thesubject has an undesirably low body weight (criterion 5). Preferably thesubject does not suffer from dementia, in particular not from seniledementia. For the purpose of the invention, persons that suffer from“senile dementia” are defined as suffering from one or more dementias.Senile dementia or dementia is considered to comprise Alzheimer'sdisease (AD).

The subject may be a prodromal dementia patient. A “prodromal dementiapatient” is a person who does not suffer from a senile dementia asdefined above, but has an increased likelihood to develop seniledementia. Likewise, a “prodromal Alzheimer patient” is a person who doesnot suffer from AD, but has an increased likelihood to develop AD. Inprinciple, any diagnostic tool for determining prodromal dementiapatient may be used. Several diagnostic tools that can be used toclassify an individual as prodromal dementia patients are describedbelow and include an accurate diagnosis of brain lesions and biochemicalproblems and careful setting of criteria. Hence, the invention isindependently directed at prodromal dementia patients or prodromalAlzheimer's patients.

In particular, persons that score positively on at least one, preferablyat least two, more preferably at least three of the following criteria,are considered to be prodromal dementia patients as defined herein:

-   -   a level of more than 350 ng Total-tau per litre cerebrospinal        fluid (CSF);    -   a weight ratio of abeta-42/Phospho-tau-181 of less than 6.5 in        CSF;    -   presence of medial temporal lobe (MTL) atrophy, existing of        volume loss of hippocampus, entorhinal cortex, or amygdala        evidenced on Magnetic Resonance Imaging (MRI) with either        qualitative ratings using visual scoring (referenced to well        characterised population with age norms) or quantitative        volumetry of regions of interest (referenced to well        characterized population with age norms)    -   presence of fronto-temporal lobe (FTL) atrophy evidenced on MRI        with qualitative ratings or quantitative volumetry;    -   a level of more than 25 pg F2-iso-prostane (F2-IsoP, isoprostane        8,12-isoiPF2alpha-VI) per mL CSF.

Further explanations of the significance of concentrations of T-tau,P-tau181, Abeta42 and F2-Isoprostane in CSF for future development ofAlzheimer's disease can be found in Hansson et al. (2006) Lancet Neurol5:228-234; and in Pratico et al. (2002) Arch Neurol 59:972-976.

In the context of this document, persons who are in a prodromal state ofAlzheimer's Disease (AD) are defined to be in a predementia stage of AD.The values of the biomarkers indicate a condition of the body, inparticular the central nervous system, wherein the risk of developingAlzheimer's disease is significantly increased, no matter whether thefinal form of Alzheimer's disease will be typical Alzheimer's disease,atypical Alzheimer's disease or mixed Alzheimer's disease. Thispredementia state of the body can be without significant clinicalsymptoms, the so called preclinical state of Alzheimer's disease,wherein a person is asymptomatic at risk for Alzheimer's disease or isexperiencing presymptomatic Alzheimer's disease. It is also important tonote that a person may experience mild cognitive impairment withouthaving an increased risk for developing Alzheimer's disease asdetermined by measuring the above-mentioned parameters (Dubois et al.(2010) Lancet Neurol, 9, 1118-1127).

The composition according the invention has its effects on body weightand/or ADL, no matter the person is a real Alzheimer's disease patient,is a prodromal Alzheimer's disease patient, is a normal elderly whichexperiences age-associated memory impairment or mild cognitive declinewithout having increased risk of developing AD, or is in the preclinicalstate of being at increased risk of developing Alzheimer's disease or adifferent dementia, like a vascular dementia.

In a specific embodiment, a prodromal Alzheimer patient can beidentified as such because he meets at least the first two criteria(total tau and ratio abeta-42/P-tau-181). More preferably, one of thethree other criteria (MTL atrophy, FTL atrophy, F2-IsoP) also applies.

In addition to or instead of one or more of the above criteria, thefollowing can be advantageously used:

-   -   reduced glucose metabolism in bilateral temporal parietal areas        of the brain, as is detectable by Positron Emission Tomography        (PET);    -   reduced glucose metabolism in the posterior cingulate cortex, as        is detectable by PET;    -   impaired blood flow in the brain as measurable by applying        Single-Photon Emission Computed Tomography (SPECT), for example        by applying the radioisotope 99 mTc-HMPAO);    -   impaired glucose metabolism in the brain as measurable by        applying SPECT;    -   abnormalities in the histology of the medial or inferior        temporal lobes as can be determined by MRI or in the rate of        glucose utilisation;    -   abnormalities in histology or glucose utilization in the        temporal parietal cortex or posterior cingulate cortex.

Abnormalities in the condition of the brain or parts thereof can beestablished by either taking the person's own condition under healthycircumstances as a reference, or, when this is not available, by takingthe average condition of a representative group (so matched for e.g.age) as a reference. The latter will occur most frequently. Bycomparison of an individual's condition with the reference situation andthe average situation when the pathological condition would have beendeveloped to its full extent, the clinician is capable of recognizing aprodromal phase. In particular an intermediate situation wherein theindividual demonstrates a deviation of x % from the value of a healthyindividual in the direction of the pathological conditions is for thepurpose of this invention considered to be a prodromal patient. Thevalue of x for the determination of blood flow and glucose metabolism is20% when determined under standardised conditions in terms of feedingand exercise.

Non-Medical Uses Directed to Body Weight or ADL

A non-medical use according to the invention is directed to increasingor maintaining body weight and/or to improving the ability to perform anactivity of daily living of a mammal, for maintaining the ability toperform an activity of daily living of a mammal, or for reducing adeterioration in the ability to perform an activity of daily living of amammal. This can be accomplished by administering the components usedaccording to the invention, wherein the components are administered tothe mammal in a diet without essentially increasing the daily caloricintake of the mammal.

A non-medical use for increasing or maintaining body weight inaccordance with the invention, is generally a healthy increase ormaintenance of the body weight, i.e. an increase not causing healthproblems, such as cardiovascular problems.

The subject in a non-medical use may in particular be an elderly human,more in particular a non-institutionalised or independently livingelderly human. Preferably the mammal is nonfrail and/or does not havedementia

In particular a the use may comprise treatment of a non-frail humancomplying with one criterion selected from an undesirably low body mass,having an undesirably low level of daily activity, and having aneurological dysfunction or treatment of a prefrail human having meetingone or two of these criterions.

The skilled person will understand what an undesirably low level ofdaily activity is, in the context of the present disclosure, see inparticular criterion 3. An undesired low degree of physical activity istypically the range of lower 20% of score. In practice this means a PASEscore of 55 or less, in particular for men a range of 30-55, preferably30-45; and for women of 27.5-55, preferably 27.5-45.

The skilled person will understand what an undesirably low body mass isin the context of the present disclosure, see in particular criterion 5(weight loss).

For instance, for an elderly person a body mass index of less than 23.5is generally undesirably low.

The elderly person to be treated may in particular have a body massindex in the range of 15-25.0, more in particular in the range of23.0-25.0. The composition may in particular be used for treating anelderly human to increase BMI to a target value in the range of 23.5 to28. with the proviso that the target value is higher than the BMI whenstarting with the use.

It is in particular considered that a use according to the invention isin particular suitable for subjects who have suffered from involuntaryweight loss in the year or two years preceding the start of consuming acomposition in accordance with the invention. Involuntary weight loss ofa subject is weight loss occurring despite the subject's aim to maintainor increase its bodyweight (on the subject's own behalf or after adviceof carer or health care professional). Such weight loss can bedetermined routinely by comparing present weight at with the weight in aperiod 1-2 years earlier and asking the subject whether he aimed tomaintain or increase his body weight. In the case of adult humans, inparticular elderly, the subject may in particular be a human, who—whenstarting with the use, has had an (involuntary) weight loss of 2-4.5 kgin the year preceding the start or 4-6 kg in the two years preceding thestart.

The skilled person will understand what a neurological dysfunction is inthe context of the present disclosure, see in particular criterion 6(neurological dysfunction). The dysfunction may in particular bediagnosed using an MMSE assessment. In particular, the frail humanhaving a dysfunction may have an MMSE assessment score below 30, more inparticular in the range of 20-26. MMSE can be determined as described byFolstein M F, Folstein S E, McHugh P R. “Mini-mental state”. A practicalmethod for grading the cognitive state of patients for the clinician. JPsychiatr Res 1975; 12:189-98.

In particular a non-medical use for increasing or maintaining bodyweight comprises one or more of: (i) increasing or maintaining lean bodyweight and (ii) increasing or maintaining muscle mass. In case thesubject is a human, the use preferably comprises increasing ormaintaining the body mass index. The non-medical use regarding ADL mayin particular be directed at treating a deterioration in ADL as a resultof normal aging. It is in particular an aim for such use to contributeto a normalisation of the activities which meets the magnitude ofactivities which complies with that of age-matched controls. Usually, anon-medical use regarding ADL involves treatment of a subject that has alowered, yet non-pathological ADL score. In particular, the subject of anon-medical use for improving the ability to perform an activity ofdaily living of a mammal, for maintaining the ability to perform anactivity of daily living of a mammal, or for reducing a deterioration inthe ability to perform an activity of daily living of a mammal accordingto the invention may have a score of more than 2 on the Katz scale, or aPASE score of at least 27.5, in particular in the range of 29-45. Inparticular, for women the PASE score may be in the range of 27.5-35; inparticular. for men, the PASE score may be in the range of 30-35.

The Katz Index of Independence in Activities of Daily Living, commonlyreferred to as the Katz ADL, is the most appropriate instrument toassess functional status as a measurement of the client's ability toperform activities of daily living independently. Clinicians typicallyuse the tool to detect problems in performing activities of daily livingand to plan care accordingly. The Index ranks adequacy of performance inthe six functions of bathing, dressing, toileting, transferring,continence, and feeding. Clients are scored yes/no for independence ineach of the six functions. A score of 6 indicates full function, 4indicates moderate impairment, and 2 or less indicates severe functionalimpairment, see ‘M. Wallace et al. ‘Try This: Best Practices in NursingCare to Older Adults, Issue Number 2, revised 2007, from the HartfordInstitute for Geriatric Nursing, New York University, College ofNursing’(http://consultgerirn.org/uploads/File/trythis/try_this_(—)2.pdf).

The ability to perform an activity of daily living may in particular beselected from the group of abilities to perform light household work(dusting, washing dishes), heavy household work (washing windows,washing floors), number of flights of stair walking, shopping, number oftimes one raises from his chair, hours sitting in a chair during theday, outdoor gardening, sports activities, paid work activities.

In a non-medical use according to the invention the components arepreferably administered to the mammal as part of a nutritionalcomposition, preferably providing a complete nutrition.

Composition According to the Invention

A composition according the invention is a nutritional composition. Whenreferring to nutritional composition, it is understood that suchcomposition has both a nutritional and a medical effect or benefit, i.e.the composition comprises macronutrients which provide a substantialsource of energy, other than the active components, in particularproteinaceous matter, fat, other than component (ii), and digestiblecarbohydrates. It preferably comprises food grade components, which makeit suitable for safe oral intake or enteral administration. Thecomponents can also be dissolved in a matrix which makes it suitable forparenteral administration. A pharmaceutical composition on the otherhand, it is understood that such composition has only a medical effector benefit, i.e. the composition comprises essentially no ingredientswhich provide a substantial source of energy, other than the activecomponents.

The composition according to the invention can have any form or physicalcondition. Preferably, it is a sterile composition or a compositionwhich comprises a defined micro-organism population, like a dairyproduct, for example which is fermented under controlled conditions or adry product to which probiotics have been added. An example of suchfermented product is a yoghurt. The composition according the inventioncan be solid, semi-solid or a drink. Such forms have been widelydisclosed in the prior art. Preferably it is a drink, though for mammalswhich experience dysphagia, a highviscosity product or a semi-solid formis preferred.

The composition according to the invention may also be a kit-of-partscomprising the components according to the invention, packed forsimultaneous or sequential administration to a person in need thereof.Hence, each component may be packed separately, or some may be packedtogether, for example in a sachet, bottle, etc.

The composition according the invention is preferably a compositionwhich complies with the criterions as set for the ruling regulations forfood for special medical purposes or of a medical food. Theseregulations are distributed by the Food and Drug Administration or asdirectives from the European Union or by recognized authorities in otherjurisdictions. In particular the composition according to the inventionprovides those nutrients and those amounts as required by the mammalbecause of the specific disease state of the mammal. These amounts ofthe active components cannot be consumed by adapting the normal diet.

In an embodiment, the composition according the invention is meant totherapeutically improve one or more of body weight, body mass index,lean body weight, muscle mass, muscle strength or muscle function. Thisimprovement can occur in elderly, in particular frail elderly. Thecomposition according to the invention can suitably be used in thenutritional management of individuals suffering from frailty symptoms orthe therapeutic management of frailty (or prefrailty), by providing acertain amount of the active components per day, and preferably perperiod of about 4 hours.

A daily amount as described herein means in particular an amount in adaily dosage unit provided by the combination of the invention. Such adaily dosage unit may be a single dosage, but it may also be dividedover two or three, or even more daily servings. If the combination,according to a preferred embodiment, is intended for administration as asingle unit, the daily amounts as described herein are preferably theamounts present in the (preferably packaged) combination unit.

It has been found that the administration of at least two componentsselected from the group of (i) a nucleoside equivalent, (ii) an ω-3polyunsaturated fatty acid selected from the group of DHA, DPA and EPA,(iii) a vitamin B selected from the group of vitamin B6, B11 and B12,(iv) a phospholipid, (v) an antioxidant, preferably selected from thegroup of vitamin C and vitamin E and (vi) a choline, with the provisothat at least component (i) or (iii) is present, is suitable for use inthe prevention or treatment of frailty in a mammal, in one embodimenttogether with or as part of a diet providing energy sources(carbohydrate, protein, fat), compared to the same isocaloric dietwithout said combination. Thus, it is concluded that the compositionaccording to the invention is effective, without needing an increase incaloric intake. Accordingly, in a specific embodiment, the effect ofsaid combination on increasing one or more of body weight, body massindex, or lean body weight is not attributed to an increase in caloricintake.

(i) Nucleoside Equivalent

The composition according to the invention may comprise a nucleosideequivalent. As used herein, nucleosides include nucleosides as suchdeoxynucleosides as such, and equivalents of nucleosides as such ordeoxynucleosides as such. Thus, when referring to a nucleoside, thisterm is meant to include the corresponding deoxynucleoside.

Equivalents in particular are compounds comprising a nucleobase, such asmononucleotides (mono-, di- or triphosphates of nucleosides),oligonucleotides, polynucleotides, nucleobases and physiologicallyacceptable derivatives thereof that may be converted into the nucleosideas such or a nucleotide as such in vivo. Examples of such derivativesinclude various esters. WO 2002/088159 (Trommsdorff GmbH) relates touridine esters, which may be used in accordance with the presentinvention. The contents of this publication regarding (deoxy)uridineesters is incorporated by reference. Such equivalents are capable ofincreasing endogenous levels of the active forms of nucleosides in bodytissues such as blood, liver and brain. Also synthetic compounds can besuitably included as nucleoside source, e.g. acylated derivatives of thenucleosides, for example triacetyl-uridine.

The composition according to the invention preferably comprises apyrimidine nucleoside or equivalent thereof, such as cytidine orequivalent thereof or a uridine or equivalent equivalent. Morepreferably, the composition according to the invention comprises auridine or an equivalent thereof, preferably at least one uridine or anequivalent thereof selected from the group consisting of uridine (i.e.ribosyl uracil), deoxyuridine (deoxyribosyl uracil), uridine phosphates(UMP, dUMP, UDP, UTP), nucleobase uracil and acylated uridinederivatives. Preferably, the composition according to the inventioncomprises an uridine phosphate selected from uridine monophosphate(UMP), uridine diphosphate (UDP) and uridine triphosphate (UTP). Mostpreferably, the composition according to the invention comprises UMP, asUMP is most efficiently being taken up by the body after oraladministration. Hence, inclusion of UMP in the composition according tothe invention enables a high efficacy at the lowest dosage, theadministration of a low volume to the subject or both. Uridinederivatives like UDP, which is readily formed from dietetic UMP, alsoappear to be important, in particular for trans-port of glycoproteinsand glycolipids within the cell and availability thereof in the cytosoland plasma membrane.

Preferably, at least 20 weight % of the uridine or an equivalent thereofin the composition according to the invention is provided by UMP, morepreferably at least 50 weight %, most preferably at least 90 weight %.

Preferably, the present use comprises the daily administration ofuridine or an equivalent thereof in a daily dosage of 0.08 to 3 g perday, preferably 0.1 to 2 g per day, more preferably 0.12 to 1 g per day.

Preferably, the present use comprises the daily administration of UMP ina daily dosage of 1.3 to 37.5 mg UMP per kilogram body weight of thesubject to be treated. The required dosages of the equivalents ofuridine on a weight basis can be calculated from the daily dosage forUMP by taking equimolar amounts using the molecular weight of theequivalent and of UMP, the latter being 324 Dalton. The daily dosage ofequivalents is preferably 3 to 115 μmol per kg body weight per day,preferably 5 to 35 μl per kg body weight per day, or 0.25 to 9 mmol,preferably 0.3 to 6, most preferably 0.45 to 2.8 mmol per day.

Preferably, the present use comprises the daily administration of acombination comprising uridine or an equivalent thereof in an amount of0.06 to 2.4 g UMP per 100 ml liquid composition, preferably 0.08 to 1.6g UMP per 100 ml liquid composition, more preferably 0.12 to 0.8 g per100 ml liquid composition. Alternatively, the optimal dose for uridinemonophosphate per 100 g dry matter is 0.18 to 7.2 g, preferably 0.24 to5.4 g and more preferably 0.36 to 2.4 g.

As a suitable cytidine equivalent cytidine can be used, for example asfree base or as a salt, as an ester, as a phosphate derivative, likeCMP, CDP or CTP, as cytosine, and as choline derivative, e.g. asciticoline. However, when both an uridine equivalent and a cytidineequivalent are included simulateously in the composition according tothe invention it is preferred that the weight ratio of the sum ofuridine and equivalents thereof to the sum of cytidine and equivalentsthereof is larger that 1.0, more preferably at least 2.0, mostpreferably more than 5.0. Although cytidine is a precursor of uridine,it is more efficient and effective to include uridine in the compositionaccording to the invention, because it passes more easily the bloodbrain barrier.

In some embodiments of the invention, useful sources of nucleosidesinclude extracts of plant, animal, bacterial, algae or yeast material,e.g. in a composition according to the invention for individuals whichdon't suffer from a kidney disease. Examples of such extracts includeheat-treated aqueous extracts from baker's yeast or brewer's yeast. In afurther preferred embodiment, the composition according to the inventionpreferably does not contain high amounts of other nucleotides. Hence,preferably the weight ratio sum of uridine and equivalents thereof toadenosine or its equivalents in the composition according to theinvention is below 0.1, more preferably below 0.01, most preferably 0.Preferably, the weight ratio of the sum of the amount of uridine andequivalents thereof to the amount of guanosine or its equivalents in thecomposition according to the invention is below 0.1, more preferablybelow 0.01, most preferably 0. Preferably, the weight ratio of sum ofuridine and equivalents thereof to inosine in the composition accordingto the invention is below 0.1, more preferably below 0.01, mostpreferably 0.

(Ii) ω-3 Polyunsaturated Fatty Acids (ω-3 PUFA's)

The composition according to the invention may comprise an ω-3polyunsaturated fatty acid (ω-3 PUFA), in particular an ω-3 long chainpolyunsaturated fatty acid (LCPUFA), more in particular selected fromthe group of docosahexaenoic acid (22:6 ω-3; DHA), docosapentaenoic acid(22:5 ω-3; DPA) and eicosapentaenoic acid (20:5 ω-3; EPA). Usefulsources include fish oil, algae oil, eggs lipids and geneticallymodified organisms.

Preferably, the composition according to the invention comprises atleast DHA, preferably DHA and EPA. More preferably, the combinationcomprises DHA and at least one precursor of DHA selected from EPA andDPA. More preferably, the composition according to the inventioncomprises DHA and EPA. The inventors recognized that only a part of theDHA incorporated in the brain originates from orally ingested DHA. Animportant part of the DHA incorporated in the brain is derived fromconversion of DPA to DHA in the brain. In a further aspect, thecomposition according to the invention preferably contains a significantamount of EPA. EPA is converted to DPA (ω-3), increasing subsequentconversion of DPA (ω-3) to DHA in the brain. Hence, the compositionaccording to the invention preferably also contains a significant amountof EPA, so to further stimulate in-vivo DHA formation.

The ω-3 PUFA's, in particular the LCPUFA's, more in particular DHA, DPAand EPA, may be provided in any form such as, but not limited to,triglycerides, diglycerides, monoglycerides, free fatty acids or theirsalts or esters, phospholipids, lysophospholipids, glycerol ethers,lipoproteins, ceramides, glycolipids or combinations thereof.Preferably, the composition according to the invention comprises atleast DHA in triglyceride form.

Preferably, the present method comprises the daily administration of 200to 5000 mg, more preferably 400 to 3000 mg, most preferably 800 to 2500mg of the sum of DHA and EPA. The proportion of (DHA+EPA) relative tothe total amount of fatty acids in the combination is preferably 5 to 50weight %, more preferably 10 to 45 weight %, most preferably 15 to 40weight %. Preferably, the present method comprises the dailyadministration of 100 to 4000 mg, more preferably 120 to 1800 mg of DHA.

Preferably, the composition according to the invention comprises 1 to 40weight % DHA based on total amount of fatty acids, preferably 3 to 36weight % DHA based on total amount of fatty acids, more preferably 10 to30 weight % DHA based on total amount of fatty acids in the compositionaccording to the invention. The composition according to the inventionpreferably comprises 0.5 to 20 weight % EPA based on total amount offatty acids, preferably 2 to 10 weight % EPA based on total amount offatty acids, more preferably 5 to 10 weight % EPA based on total fattyacids. The weight ratio of DHA to the sum of EPA and DPA is preferablylarger than 1.0, more preferably 1.2 to 10, more preferably 2 to 8. Theabove-mentioned ratios and amounts take into account and optimiseseveral aspects, including taste (too high LC-PUFA levels reduce taste,resulting in a reduced compliance), balance between DHA and precursorsthereof to ensure optimal effectiveness in relation to maximum dosageand possibility of product formulations such as liquid form, bar orcapsule.

In one embodiment, the composition according to the invention contains alow amount of arachidonic acid (AA; 20:4 ω-6). Arachidonic acid isbelieved to counteract the effects of the composition according to theinvention. The present subjects normally ingest sufficient AA, orprecursors thereof, and an excess daily dosage may stimulateinflammatory responses, inhibiting daily activities. Preferably, theweight ratio DHA/AA in the composition according to the invention is atleast 5, preferably at least 10, more preferably at least 15, up to e.g.100. Preferably, the weight ratio EPA/AA is at least 2. The presentmethod preferably comprises the administration of a compositioncomprising less than 5 weight % AA based on total amount of fatty acids,more preferably below 2.5 weight %. The ω-6/ω-3 weight ratio oflong-chain polyunsaturated fatty acids with at least 20 carbon atoms inthe composition according to the invention is advantageously below 0.5,preferably below 0.2. If the long-chain polyunsaturated fatty acids with18 carbon atoms are also included in the ratio, the preferred ω-6/ω-3weight ratio is 0.05 to 1, more preferably 0.1 to 0.6, most preferably0.15 to 0.4.

(iii) Vitamin B

In an embodiment, the composition according to the invention comprisesat least one vitamin B selected from the group of vitamin B6, vitamin B9and vitamin B12. Vitamin B6 includes pyridoxine, pyridoxal,pyridoxamine, and pyridoxine salts, e.g. the hydrochloride or phosphatesalt. Vitamin B9 is also known as folic acid or folate. Vitamin B12 isalso known as cobalamines.

In particular, good results have been achieved with a combinationcomprising vitamin B6, vitamin B12 and vitamin B9. Advantageously,vitamin B12 and vitamin B9 are included because low plasma B12 orvitamin B9 levels are a risk factor for the developwent of Alzheimer'sdisease.

It should be noted that one or more other vitamins of the vitamin Bfamily may be present in a composition (for use) according to theinvention, that do not form part of the active components mentionedunder ‘(iii) vitamin B’ for use in accordance with the invention. Suchother vitamins B include in particular vitamin B1 (thiamine), vitamin B2(riboflavin), vitamin B3 (niacin or niacinamide), vitamin B5(pantothenic acid), and vitamin B7 (biotin).

The vitamin B is to be administered in an effective dose, which dosedepends on the type of vitamin B used. As a rule of thumb, a suitableminimum or a maximum dose may be chosen based on known dietaryrecommendations, for instance as recommended by Institute of Medicine(IOM) of the U.S. National Academy of Sciences or by ScientificCommittee on Food (a scientific committee of the EU), the informationdisclosed herein and optionally a limited amount of routine testing. Aminimum dose may be based on the estimated average requirement (EAR),although a lower dose may already be effective. A maximum dose usuallydoes not exceed the tolerable upper intake levels (UL), as recommendedby IOM.

If present in the nutritional or pharmaceutical composition according tothe invention, the vitamin B6 is usually present in an amount to providea daily dosage in the range of 0.5 to 100 mg, in particular in the rangeof 0.75 to 25 mg, more in particular in the range of 0.9 to 5 mg Ifpresent in the nutritional or pharmaceutical composition according tothe invention, the vitamin B12 is usually present in an amount toprovide a daily dosage in the range of 0.5 to 1000 μg, in particular inthe range of 1 to 100 μg, more in particular in the range of 1.5 to 10.If present in the nutritional or pharmaceutical composition according tothe invention, the vitamin B9 is usually present in an amount to providea daily dosage in the range of 50 to 5000 μg, in particular in the rangeof 150 to 1000 μg, more in particular in the range of 200 to 1000 μg

In a preferred embodiment of the invention, the active components areincluded in a drink, preferably having a volume of about 125 ml, or inan alternative preferred embodiment in a product having a dry masscontent of about 30 g, per packaging each of them being for consumptiononce a day. This means that the amounts per daily dose as mentionedabove can be recalculated to a concentration per millilitre, by dividingthe above-mentioned value with 125, or to a concentration per g dry massof the product by dividing by 30.

This way of calculation also applies to the other active components (i)to (vi) in the composition according to the invention when a desireddose per daily dose is disclosed.

(iv) Phospholipids

The composition according to the invention may comprise a phospholipid.As used herein, the term phospholipid includes lyso-phospholipids,de-acylated phospholipids and glycerophospholipids. It is preferred toinclude a phospholipid which is capable of increasing chylomicronsformation in elderly after administration of triglyceride lipids and canprovide useful fatty acids. In particular, the phospholipid is selectedfrom the group of phosphatidylcholine(PC), phosphatidylethanolamine(PE), phosphatidylserine (PS), phosphatidic acid (phosphatidate),phosphoinositides (such as phosphatidylinositol (PI),phosphatidylinositol phosphate, phosphatidylinositol bisphosphate,phosphatidylinositol triphosphate) and sphingomyelin. In particular, thecombination according to the invention comprises at least two differentphospholipids selected from the group consisting of phosphatidylserine,phosphatidylinositol, phosphatidylcholine and phosphatidylethanolamine.Preferably the combination according to the invention comprisesphosphatidylcholine, phosphatidylethanolamine and phosphatidylserine.Good results have been achieved with a combination ofphosphatidylcholine (PC) and phosphatidylserine (PS), preferably in aweight ratio of 3:1.

For instance, lecithin may be used as a source for the phospholipids.Optionally the phospholipids are fortified with one or morephospholipids, such as a ceramide, a sphingolipid or a specificphospholipid, such as a phosphatidylcholine.

The phospholipid is to be administered in an effective dose. Usually,the total phospholipid daily dosage is in the range of 50 to 5000 mg, inparticular in the range of 100 to 2000 mg, more in particular in therange of 150 to 1200 mg

Inclusion of phospholipids further beneficially improves membranefunction, thereby enabling an improved functioning of the differentparts of the brain that may be affected in prodromal subjects.Furthermore, the phospholipids improve stability and shelf life of thecomposition according to the invention. Phospholipids further enable themanufacturing of palatable compositions. Also, phospholipids are asource for choline and prevent the decline in plasma choline levelsafter exercise. Choline is necessary for the formation of acetylcholine,a neurotransmitter involved in learning and memory and in the activationof muscles. These advantages are already achieved at relatively lowphospholipid levels.

(v) Anti-Oxidant

The composition according to the invention may comprise an antioxidantselected from the group of vitamin C, vitamin E and selenium. Thevitamin C may be present as free acid (ascorbic acid) or as a salt, e.g.sodium ascorbate or potassium ascorbate. Suitable sources of vitamin Einclude (alpha-)tocopherol and tocotrienol. Suitable sources of seleniuminclude selenate and selenite.

The anti-oxidant is to be administered in an effective dose. As a ruleof thumb, a suitable minimum or a maximum dose may be chosen based onknown dietary recommendations, for instance as recommended by theInstitute of Medicine (IOM) of the U.S. National Academy of Sciences orby the Scientific Committee on Food (a scientific committee of the EU),the information disclosed herein and optionally a limited amount ofroutine testing. A minimum dose may be based on the estimated averagerequirement (EAR), although a lower dose may already be effective. Amaximum dose usually does not exceed the tolerable upper intake levels(UL), as recommended by IOM. If present in the combination, vitamin C isusually present in an amount to provide a daily dosage in the range of20 to 1200 mg, in particular in the range of 30 to 400 mg, more inparticular in the range of 35 to 120 mg. If present in the nutritionalor pharmaceutical composition according to the invention, the vitamin Eis usually present in an amount to provide a daily dosage in the rangeof 8 to 200 mg, in particular in the range of 20 to 140 mg, more inparticular in the range of 35 to 100 mg.

If present in the nutritional or pharmaceutical composition according tothe invention, the selenium is usually present in an amount to provide adaily dosage in the range of 40 to 400 μg, in particular in the range of50 to 200 μg, more in particular in the range of 55 to 80 μg.

Optionally one or more antioxidants may be present other than (v) theantioxidant selected from the group of vitamin C, vitamin E andselenium.

(vi) Choline

The nutritional or pharmaceutical composition according to the inventionmay comprise a choline. Choline refers to the various quaternaryammonium salts containing the N,N,N-trimethylethanolammonium cation.More specifically, choline is selected from the group of the cholinecation, choline salts or esters, such as choline chloride, cholinebitartrate, choline stearate, or the like, or compounds that dissociateto choline, such as choline alfoscerate, sphingomyelin,cytidine-diphospho-choline or citicoline or CDP-choline,acylglycerophosphocholines, e.g, lecithin, lysolecithin,glycerophosphatidylcholine, and any mixture thereof. It is preferred toinclude a choline salt or choline alfoscerate into the compositionaccording to the invention.

In particular, choline is to be administered in an amount to provide adaily dosage of 100 to 4000 mg, more in particular of 200 to 2000 mg.

Furthermore, the nutritional or pharmaceutical composition according tothe invention may comprise one or more further micronutrients, forinstance one or more micronutrients selected from the group of vitamins,minerals, and trace elements, taurine and inositol.

Protein and Energy Content

The composition, preferably the nutritional composition according to theinvention allows improvement of BMI, or LBM, or frailty, withoutdemanding to consume large amounts of protein or additional energy.Actually, the amount of energy in the composition according to theinvention can remain limited to a value of less than 400 kcal (1680 kJ),preferably less than 280 kcal (1178 kJ) or more preferably less than 210kcal (882 kJ), all expressed per daily dose for an adult human. Theamount of energy is not needed to create the effect (as can be concludedfrom the experiment, which has an isocaloric control), but is simply theresult of incorporating the active components into a small sized foodproduct, which is thus used as a vehicle. In one embodiment, thecomponents (i) to (v) are included in a pharmaceutical compositionaccording to the invention having an energy content per serving unit ofless than 130 kcal (546 kJ) or preferably less than 80 kcal (336 kJ).

In one embodiment, the amount of active components (defined ascomponents (i) to (v)), which is needed to achieve the effect on BMI,etc, delivers more than 50%, preferably more than 58%, most preferably62 to 88% of the total amount of calories of the composition as claimed.For the calculation of energy, the inventors use 9 kcal (37.8 kJ) per gof lipids or phospholipids, zero kiloJoule per g of nucleosides,vitamins and a choline equivalent, 4 kcal (16.8 kJ) per g of protein anddigestible carbohydrate and 2 kcal (8.4 kJ) per g of fibre.

The protein amount in the composition according to the invention, ifpresent, can remain relatively low, which can have important advantagesto the largest part of individuals which suffer from weight loss orsymptoms of frailty. In particular, it is preferred that compositionaccording to the invention should not impair normal eating patterns,allow manufacture of a palatable product and not induce heartburn orgastrointestinal discomfort after consumption thereof. The compositionaccording the invention appears effective, also when the concentrationof protein in the composition according to the invention remains below11 g per 100 ml and preferably below 9, more preferably 3 to 8.4 g, andmost preferably 5.2 to 8.2 g per 100 ml of the composition according tothe invention.

For concentrates, semi-dry and dry products, it is more convenient toexpress the concentration of protein on gram dry matter basis. Theamount of protein is in these cases usually less than 400 mg, preferablyless than 360 mg, more preferably 100-340, most preferably 150 to 330 mgper g dry matter. Simple proteins can be used in these amounts like milkprotein. These technical features of the composition according to theinvention result in good compliance with the feeding protocol with suchcomposition according to the invention and in very little adaptation ofthe normal diet after the composition according to the invention havebeen consumed according their recommended use.

In order to avoid an undesired satiating effect, especially in elderly,the amount of caseinates preferably is 4.5 weight % or vol % or less forliquid formula, and more preferably 0.5 to 4.0 weight % or vol % or mostpreferably 0.8 to 3.3 weight % or vol %. Therefore, but also forefficacy reasons, it is preferred to include a non-caseinate in thecomposition according to the invention, which is elaborated below.

The effect of the active components (specific combinations ofnucleosides, LC-PUFAs, phospholipids, vitamins and a choline equivalent)allows efficacy by administering a nutritional composition according tothe invention with the minimum amount of food volume, e.g. less than 150ml per serving unit, which is also important because elderly, andespecially frail elderly experience much earlier satiety when consumingfood.

In one embodiment of the invention the actives are provided to theconsumer, in a ready to use serving unit which provides 15 to 160 g ofthe effective composition according to the invention.

It has been suggested before, that additional protein of specificquality could improve LBM or increase body weight in elderly. Focus inthe most relevant papers in this field is on the amount of protein(which should preferably be more than a few dozen g additional proteinper daily dose), inclusion of L-leucine or including a large portion ofessential amino acids in the protein amount, e.g. more than 15 g of thepure crystalline amino acids. Complying to such diet can be verydemanding to many frail elderly, also because the taste of free aminoacids is often considered as offensive or because consumption of suchlarge amounts of protein has a significant impact on the consumption ofregular diet.

The invention therefore provides a solution for the problem that anundesired amount of additional protein has to be administered foranabolic purposes, i.e. the improvement in BMI of elderly and itincreases the improvement of the brain function as observed in frailelderly by consuming the combination of one or more of the activecomponents (i) to (v) according to the invention.

The protein amount preferably comprises a non-caseinate protein forsupporting an effect of the composition according the invention on BMIin frail elderly. In particular, specific whey protein relatively low inphosphorous, fish proteins, in particular cod protein, or a proteinderived from eggs and proteins derived from vegetables, like potato,soy, pea, beans, lupin, quinoa and amaranth appeared suitable. Theproteins can be intact, either heat-treated or non-denatured, or bepartially hydrolyzed. Hydrolyses of the intact protein aims to improveits solubility, but degree of hydrolyses should be kept to the minimum,preferably to a degree of hydrolyses between 2 and 12, in order tomaintain good organoleptic properties of the ready to use compositionaccording to the invention. In a preferred embodiment, the amount ofnon-dairy protein is more than 21 weight %, more preferably more than 25weight %, most preferably more than 42 weight %, in particular more than51 weight % of the protein amount.

Suitable whey proteins include those which have a phosphorous contentless than 400 mg/l when 100 g of the protein is dissolved in one litreof water. Preferably, this phosphorous content is 70 to 340 mg/l. Theamount of protein can be calculated from the label of the product, or,when this is impossible or not justified by measuring Kjeldahl nitrogenby a method accepted as preferred in the prior art for the specificmatrix, and multiplying this by 6.25 for mixtures of proteins andpeptides.

If dairy proteins are included, it is preferred to include a wheyprotein. Such protein is preferably enriched in serum albumin or alphalactalbumin. Such dairy amount also preferably comprises a lactoferrin.The concentration of alpha-lactalbumin as fraction of all whey proteinsis preferably more than 25 weight %, that of serum albumin 5 to 12weight %. The concentration of lactoferrin is preferably in the range0.25 to 3 weight %, preferably 0.29 to 1.4 weight %, more preferably0.34 to 1.2 weight % of the protein amount.

In cases where the fatty acids comprise that much omega 3 fatty acidsthat the ratio of the weight amounts of omega 3 to omega 6 exceed 5, theamount of whey protein is preferably less than 50 weight % of theprotein amount, in order to keep the satiating character of thecomposition according to the invention as low as possible, whilemaintaining efficacy of the composition according to the invention.

It is also useful to include non-essential amino acids or their salts oresters. Examples of suitable amino acids include serine and asparticacid. These amino acids can be administered as L-isomer or as a racemicmixture of L and D isomers of the particular amino acid. The amountaspartate plus asparagine in the composition according to the inventionis preferably more than 8.4, more preferably 9.0 to 16, most preferably9.5 to 15 g per 100 g amino acids in the composition according to theinvention. The amount of serine in the ready to use compositionaccording to the invention is preferably more than 4.1 g per 100 g aminoacids. The presence of these two amino acids in the formula is thoughtto be at least partially responsible for the anabolic character of theformula and the observed efficacy in treating symptoms of frailty.Increasing the concentrations to the indicated amounts in the preferredembodiment increases their effect. In this respect, the effect onneurological symptoms in the low BMI elderly includes the effect ondepressed mood, stamina and the activities of daily living. Theinventors believe that an effect on metabolic pathways is responsiblefor this, in particular an effect on glucose metabolism and geneexpression and not the amount of calories or amount of protein that areprovided by the composition according the invention.

The selected types and amounts of protein appeared to have theunexpected advantage in that long term administration to personsexperiencing frailty or low body weight, especially in the agedpopulation achieved better results in increasing BMI, lean body mass orbody weight and muscle function, muscle strength and muscle mass, thanmost high protein dairy protein based formula, fortified with essentialamino acids, and demonstrated less adverse effects in sensitive persons.

It is of importance that in a preferred embodiment, the protein amountcontributes to a better functioning of metabolism in order to supportthe maintenance of BMI, and lean body mass, and other symptoms offrailty, like exhaustion and fatigue and neurological function.Therefore, the protein preferably comprises a whey protein and morepreferably a whey protein and a vegetable protein.

In a preferred embodiment, the osmotic value of the compositionaccording to the invention is as low as possible, in order to facilitateeasy stomach emptying. In a preferred embodiment, the compositionaccording to the invention demonstrates an osmolality below 450 mEq/l.

In addition, the buffer strength of the composition according to theinvention preferably low, in order to achieve rapid digestion and guttransfer of the composition according to the invention afterconsumption. This is done by using the amounts and types of proteins asindicated above and by preventing the use of high salt loads, inparticular of citrates and phosphates. The amount of phosphorous in thecomposition according to the invention is preferably less than 150 mg,more preferably 20 to 110 mg, most preferably 50 to 72 mg per 100 ml. Inone embodiment, the nucleotides in the composition according to theinvention, like a uridine phosphate, or cytidine phosphate are replacedby their base. In a preferred embodiment, the composition according tothe invention comprises a nucleobase and a nucleoside or nucleotide. Ina preferred embodiment, the ratio of the weight amount of nucleobase tothe sum of the corresponding nucleosides and nucleotides is more than0.06, preferably 0.2 to 0.9.

The amount of organic acids, like citrates, is preferably less than 2,more preferably less than 1.2 weight %, most preferably 0.1 to 0.9weight % of the digestible carbohydrate amount. These features are inparticular relevant when the elderly suffer from diagnosedanchlorhydria. This is a major problem in elderly and in particular ininstitutionalized elderly or elderly having a BMI under 23.5 kg/m2 orfrail elderly.

In a preferred embodiment, the composition according the invention is aliquid formula having a viscosity of less than 60, more preferably 2 to30 mPa·s, measured at 20 degrees ° C. As used herein, the viscosity isthe viscosity as measurable using a Anton Paar Physica MCR301 rheometerwith aCP50-1/PC cone (diameter 50 mm, 1° difference between middle andoutside) at 20° C. at 100s⁻¹.

Dosage Form

Further, one or more additional ingredients may be present that arecommonly used in the prior art, dependent on the form—nutritional orpharmaceutical composition—in which the combination is provided.

If the dosage form is a pharmaceutical composition, the pharmaceuticalcomposition may comprise one or more excipients known in the prior artto provide a pharmaceutical composition in a dosage form of choice. Thepharmaceutical composition is preferably for enteral application (orallyor via tube-feeding). Examples of solid formulations are tablets,capsules (e.g. hard or soft shell gelatine capsules), pills, sachets,powders, granules and the like which contain the active ingredientstogether with a conventional carrier. Any conventional carrier materialcan be utilized. The carrier material can be organic or inorganic inertcarrier material suitable for oral administration. Suitable carriersinclude water, gelatine, gum Arabic, lactose, starch, magnesiumstearate, talc, vegetable oils, and the like. Additionally, additivessuch as flavouring agents, preservatives, stabilizers, emulsifyingagents, pH-buffers and the like may be added in accordance with acceptedpractices of pharmaceutical compounding. While the individual activeingredients are suitably administered in a single composition they mayalso be administered in individual dosage units.

If the dosage form is a nutritional composition, the compositiongenerally comprises at least one macronutrient for providing(additional) energetic value to the nutritional composition. Themacronutrient may suitably be selected from the group of proteinaceousmatter (proteins, peptides, amino acids), fat, other than component(ii), and digestible carbohydrates.

Suitable proteinaceous matter, lipids and carbohydrates, and suitableconcentrations of the macronutrients may be based on known dietaryguidelines for food products, in particular for food products for theelderly. Suitable formulations may e.g. be based on known commerciallyavailable clinical foods, or foods advertised for feeding elderly peopleor for feeding people suffering from dementia.

Regarding the lipid, preferably one or more triglycerides are present.These may be selected from vegetable oils and fats and animal oils andfats.

Regarding the digestible carbohydrates, these may in particular beselected from digestible pentoses, digestible hexoses digestibleoligosaccharides, e.g. digestible disaccharides and digestibletrisaccharides. and digestible polysaccharides (e.g. starch). Morespecifically one or more digestible carbohydrates may be chosen selectedfrom the group of galactose, mannose, ribose sucrose, trehalose,palatinose, lactose, maltodextrose, maltose, glucose, fructose,including oligomers and polymers thereof.

Optionally, a nutritional composition according to the inventioncomprises one or more non-digestible carbohydrates (dietary fibres) suchas oligosaccharides. As used herein, the term oligosaccharides inparticular refers to saccharides comprising 3 to 25 monosaccharide unitsper molecule. The oligosaccharide(s) may in particular be selected fromthe group of fructo-oligosaccharides (FOS), galacto-oligosaccharides(GOS), trans-galacto-oligosaccharides (TOS), xylo-oligosaccharides(XOS), soy oligosaccharides, and the like. Optionally, also highermolecular weight compounds such as inulin, resistant starch and the likemay be incorporated in the composition according to the invention.

Further, the nutritional composition may comprise a probiotic.

Further, the nutritional composition may comprise one or more additivescommonly used in food technology, such as one or more additives selectedfrom the group of flavourings, stabilisers, preservatives, colourants,emulsifiers, pH-buffers etc.

The nutritional composition for use in a accordance with the inventionmay be a solid composition. a semi-solid composition (such as a paste ora gel) or a liquid composition, such as a beverage of a drinkable foodproduct.

The nutritional composition according to the invention may in particularbe intended for enteral administration (orally or by tube feeding).Alternative forms of administration may be applied, in particularparenteral administration. The skilled person will be able to formulatea suitable product for parenteral administration, in particular bypreventing inclusion of non-endogenous proteinaceous material which mayinduce an allergic reaction or other adverse effects. The administrationmay be carried out based on a manner known per se for a specific type ofnutritional composition.

In particular, the nutritional composition may be selected from thegroup of spreads; yoghurts, custards, ice-creams, butter, and otherdairy products; dairysubstitute products; drinks, such as fruit drinks;candy bars; cookies, cakes and other bakery products; and drinkablefoods.

The total energetic value of the composition may be chosen within widelimits and may range, e.g., from 0.2 to 4 kcal/g. In particular, theenergetic value may be at least 0.4 kcal/g, more in particular at least0.8 kcal/g. In particular, the energetic value may be 5 kcal/g or less,more in particular 3 kcal/g or less.

In case the nutritional composition is a fluid, it usually has anutritional value of at least 20 kcal/100 ml, preferably of at least 50kcal/100 ml, in particular of at least 75 kcal/100 ml or at least 100kcal/100 ml. For a fluid composition the nutritional value is usually300 kcal/100 ml or less, in particular 200 kcal/100 ml or less, more inparticular 150 kcal/100 ml or less.

Suitable dosage forms, active ingredients, further components that maybe coadministered and ways of administration are as described for thenutritional or pharmaceutical composition as described herein above, theclaims, or the examples herein below.

The vitamin B, the phospholipid, the antioxidant and—if present—furtheractive ingredients, may be administered under the supervision of amedical specialist or be selfadministered.

Specific embodiment: nutritional composition (per se)

As mentioned above, the invention also relates to a nutritionalcomposition comprising (i) at least one component selected from thegroup of uridine and iuridine monophosphate, (ii) DHA and EPA (which maybe present in bound for e.g. as a triglyceride ester) (iii) a vitamin B,(iv) a phospholipid, v) an antioxidant, and (vi) a choline. Preferredsources, preferred specific compounds for each group, concentrations,dosages and other product properties may generally be as describedherein above. The nutritional composition according to the inventionusually also comprises, protein. Further, digestible carbohydrate andfibre. are usually present. Preferably, the nutritional compositioncomprises i-a) the nucleoside uridine and i-b) the nucleotide uridinemonophosphate. i-a) Uridine and i-b) uridine monophosphate arepreferably present in a weight to weight ratio in the range of 0.2:1 to0.7:1. The presence of both i-a) uridine and i-b) uridine monophosphate,especially in said ratio, is in particular advantageous because itprovides a more uniform bioavailability after oral administration, whichincreases the number of responders to the composition (used) accordingto the invention (subjects reacting positively on treatment with acomposition in accordance with the invention), without any unacceptableadverse effects. In addition, the nucleoside uridine may decreasesactivation of P2Y receptors in the gut.

In a preferred embodiment, the total content of uridine plus uridinemonophosphate is in the range of 5-30 mg per gram dry weight, morepreferably in the range of 8-20 mg per gram dry weight, in particular inthe range of 10-18 mg per gram dry weight.

The total content of uridine plus UMP as a weight percentage of totalnucleoside equivalents preferably is more than 28 wt. %, more preferably40-100 wt. %, most preferably 60-100 wt. %, in order to obtain aselective effect of the nucleotide fraction in the product of theinvention, such as in order to avoid triggering an undesired effect inthe enterocytes or liver or the enteral nervous system, due toactivation of receptors, for example the P2X or P2Y receptors, byadenosine-based or guanosine-based nucleotides.

The weight to weight ratio of UMP to GMP (guanosinemonophosphate)preferably is more than 10. The weight to weight ratio of UMP to UMP(inosine monophosphate preferably is more than 10.

In a specific embodiment, the nutritional composition according to theinvention, comprises 3-14 mg EPA per gram dry matter, preferably 5-10 mgEPA per gram dry matter and 12-56 mg DHA per gram dry matter, preferably2.5-20 mg DHA per gram dry matter. Preferably, the sum of DHA and EPA is5-50 wt. % based on total fatty acids.

A composition according to the invention preferably has a lowarachidonic acid (AA), content, if present at all, especially in anembodiment wherein on or more of component (ii) ω-3 PUFAs selected fromEPA, DHA and DPA are present. AA is thought to have a disadvantageouseffect on the effectiveness of these components in a use according tothe invention. In view thereof, the weight to weight ratio of the sum ofDHA+DPA+EPA to AA preferably is higher than 5, in particular 6 orhigher, more in particular 12 or higher. In a particularly preferredembodiment, the weight to weight ratio of DHA to AA is higher than 5.The ratio long chain ω-6 PUFAs to long chain ω-3 PUFAs preferably is0.05 to 1. The term ‘long-chain’ is used herein for PUFA's having acarbon chain of at least 20 carbon atoms.

The ratio [uridine monophosphate+uridine]/[phospholipds] of anutritional composition according to the invention is usually less than5.9, preferably 0.15-4, in particular 0.20-2.4, more in particular0.25-0.71. A relatively low ratio of [uridinemonophosphate+uridine]/[phospholipds] is in particular preferred in acomposition comprising a protein. In particular in such embodiment, itcontributes to a better efficacy with respect to a use of the invention,in particular with respect to providing a palatable effective product adecrease of uridine concentration and an increase of phospholipidconcentration allows better tasting while maintaining efficacy. Arelatively low ratio is also is advantageous for improving thepalatability, especially during shelf-life.

The nutritional composition of the invention usually has an energydensity of less than 13 kcal per gram dry matter, preferably of 3-9.3kcal per gram dry matter, more preferably of 4.0-7.0 kcal per gram drymatter.

In a specific embodiment, the nutritional composition according to theinvention, comprises phosphatidylcholine (PC). In such embodiment theweight to weight ratio phosphatidylcholine to choline is usually morethan 0.1, preferably more than 0.26, in particular 0.30-6, morepreferably 0.36-3. Herein, the amount of choline in grams is to becalculated as the molar contribution of choline as provided by allcholine sources (when orally digested and assuming 100% bioavailability,including PC), times the molecular weight of choline (104 g/mol).Herein, the molecular weight of PC 810 gram/mol. So for example,including 400 mg choline chloride and 200 mg phosphatidylcholine and 200mg PL's other than PC would then result in a weight ratio of PC tocholine of 200/[(104/139.6)×400+(104/810)×200]=200/[298+25.7]=0.62

The presence of PC is in particular preferred as a source for choline,because less PC is required than equimolar choline ingredient (i.e.N,N,N-trimethylethanolammonium cation) for obtaining the same cholineconcentrations in blood. Herewith choline (salt) content can be reduced,whilst still providing a choline source. Advantageous thereof includeavoiding a fishy odour of product and/or subject treated with theproduct; avoiding irritation of the mucous membranes in case ofxerostomia.

The nutritional product usually comprises a protein. The protein contentis preferably less than 400 mg per gram dry matter, more, preferably100-340 mg protein per gram dry matter. A relatively low protein contentis preferred to decrease consequences on diet intake. In particular, arelatively low protein content is desired in view of a satiating effecta high protein content has, which may cause the subject to consume aninsufficient amount of the nutritional product. For improvedpalatability and/or for improving brain function. In a liquid product,the protein content preferably is less than 11 g/100 ml, more preferably5.2-8.2 g/l. In a specific embodiment, the protein content is more than7 g/100 ml.

In an advantageous embodiment, the nutritional composition comprises atleast a whey protein. In a liquid product, the dairy protein content(whey protein, casein, caseinate) preferably is less than 4 wt./vol %.

In an advantageous embodiment, the nutritional composition according tothe invention comprises a protein selected from the group of fishproteins (in particular cod protein), egg-protein and vegetableproteins. If present, the total content of non-dairy protein is usuallymore than 21 wt. % preferably 22-80 wt. %, in particular 25-40 wt. %,based on total protein content. Non-dairy proteins, such as vegetable,fish or egg protein is an advantageous protein source, amongst othersbecause they are less satiating than dairy proteins. Another reason toinclude such non-dairy protein is an improved endocrine response action,which results in good postprandial glucose response. compared to a dairyprotein, in particular compared to casein/caseinate.

A vegetable protein may in particular be selected from the group ofpotato protein, soy protein, pea protein, beans protein, lupin protein,quinoa protein and amaranth protein.

A composition comprising whey protein and amaranth or pea protein is inparticular suitable for increasing BMI. The weight ratio whey protein tothe sum of amaranth and pea protein may in particular be 50:50 to 90:10,more in particular 60:40 to 80:20.

A composition comprising whey protein, soy protein and wheat protein isin particular suitable for increasing ADL in subjects suffering fromearly physical exhaustion after exercise. When present in combination,the whey protein content preferably is 30-70 wt. % of the proteinfraction, the pea protein fraction preferably is 15-35 wt. % of theprotein fraction, and the soy protein fraction preferably is 15-35 wt. %of the protein fraction. One or more other proteins from other sourcesmay be present in a product comprising proteins from these three proteinsources, e.g. casein, usually in a total concentration of up to 40 wt. %of the protein fraction.

The dairy protein or the non-dairy protein may be non-hydrolysed or maybe partially hydrolysed. The degree of hydrolysis may in particular be2-12.

In a specific embodiment, a composition (for use) according to theinvention comprises at least one amino source providing L-serine and/orL-aspartic acid. The amino acid source can be selected from free aminoacids, including salts thereof, peptides (oligopeptides, polypeptides,proteins), comprising and L-serine unit and/or L-aspartic acid units. Ifpresent, the L-serine content preferably is higher than 4.1 g per 100gram amino acids, including amino acids in peptides and other compoundsproviding an amino acid when digested. If present, the L-aspartic acidcontent preferably is 8.4-15 g per 100 gram amino acids including aminoacids in peptides and other compounds providing an amino acid whendigested.

Preferably, the nutritional composition comprises 0.15-0.5 g digestiblecarbohydrate per gram dry weight, in particular 0.20-0.40 g digestiblecarbohydrate per gram dry weight. Preferably, the digestiblecarbohydrate fraction provides glucose, fructose and galactose (presentas monosaccharide or in oligo/polysaccharide form).

Preferably 0.01-0.1 g fibre per g dry weight is present in a compositionaccording to the invention. In particular, the fibre content may be inthe range of 0.02-0.08 g per g dry weight.

The lipid content in a nutritional composition according to theinvention preferably is 0.15-0.3 g lipids per gram dry weight.

Further, the composition may comprises additional vitamins and/orminerals.

In particular good results have been achieved with a liquid compositionaccording to the invention.

The liquid composition usually has a dry matter content of 15-30 g per100 ml. The dry matter content preferably is 24 g per 100 ml or less, inorder to aid water homeostasis, in particular 16-24 g per 100 ml, morein particular 17-22 g per 100 ml.

The liquid composition preferably has an osmolarity of less than 450mEq/l, in particular of 120 to 450 mEq/l.

The viscosity of a liquid nutritional composition according to theinvention is usually less than 200 mPa·s

The liquid composition may in particular be packaged as a unit dosepackaging, which may in particular have a liquid composition content inthe range of 50-250 ml, more in particular in the range of 100-150 ml.

In a specific embodiment, the composition is a powder, in particular apowder that is reconstitutable with water to provide a liquid productaccording tot the invention

The invention will now be illustrated by the following examples and theexperimental part, without being bound or restricted thereto.

EXPERIMENTAL

For Examples 1-4, mice were used that were 3 months old at the start ofthe experiment. In the test period all mice were considered to behealthy by the Ethical Committee.

Example 1

APP/PS1 mice, were provided with a diet enriched with DHA and UMP(intake per day: DHA=22.8 mg; UMP=23.1 mg) or with a control diet for 3months The two diets were isocaloric and differed only with respect toDHA and UMP content The amount of fat, carbohydrates and protein was thesame between diets. During the 3 months of diet intervention body weightwas monitored as was food intake.

Results.

Mice fed the enriched diet showed—on average—a 17.5% increase in bodyweight after 3 months compared to 14% for the control mice. Food intakewas slightly lower in the group which were fed the enriched diet (onaverage 2.88 gram per day) compared to control mice (on average 3.08gram per day).

Conclusion.

mice showed an increase in body weight when fed with the compositionaccording to the invention (the ω-3 polyunsaturated fatty acid DHA andthe nucleoside UMP), not attributed to a caloric increase in bodyweight.

Example 2

APP/PS1 mice, were provided with a diet enriched with B-vitamins (B6,B12 and folic acid; intake per day: B6=0.1 mg; B12=0.11 μg; folicacid=18.1 μg), phospholipids (lecithin; intake per day: 12.4 mg) andantioxidants (vitamin C, vitamin E, selenium; intake per day: vitaminC=4.8 mg; vitamin E=4.5 mg; selenium=3.2 μg) or with a control diet for3 months. The two diets were isocaloric and differed only with respectto B-vitamins, phospholipids and antioxidants content. The amount offat, carbohydrates and protein was the same between diets. During the 3months of diet intervention body weight was monitored as was foodintake.

Results.

Mice fed the B-vitamins+phospholipids+antioxidants enriched diet showeda 18% increase in body weight after 3 months compared to 14% for thecontrol mice. Food intake was slightly lower in theB-vitamins+phospholipids+antioxidants group (on average 2.86 gram perday) compared to control mice (on average 3.08 gram per day).

Conclusion.

mice showed an increase in body weight when fed with the compositionaccording to the invention (B vitamins, a phospholipid, andantioxidants), not attributed to a caloric increase in body weight.

Example 3

APP/PS1 mice, were provided with a diet enriched with DHA+UMP (intakeper day: DHA=22.8 mg; UMP=23.1 mg) (as in Example 1), B-vitamins (B6,B12 and folic acid; intake per day: B6=0.1 mg; B12=0.11 μg; folicacid=18.1 μg), and phospholipids (lecithin; intake per day: 12.4 mg) orwith a control diet for 3 months. The two diets were isocaloric anddiffered only with respect to DHA, UMP, B-vitamins and phospholipidscontent. The amount of fat, carbohydrates and protein was the samebetween diets. During the 3 months of diet intervention, body weight wasmonitored as was food intake.

Results.

Mice fed the enriched diet showed a 20% increase in body weight after 3months compared to 14% for the control mice. Food intake was the same inthe ω-3 PUFA+nucleoside+B-vitamins+phospholipids group (on average 3.02gram per day) compared to control mice (on average 3.08 gram per day).

Conclusion.

mice showed an increase in body weight when fed with the compositionaccording to the invention (ω-3 polyunsaturated fatty acids, anucleoside, B vitamins, and phospholipids), not attributed to a caloricincrease in body weight.

Example 4

APP/PS1 mice, were provided with a nutritional composition comprisinguridine-5′-monophosphate (intake per day: UMP=23.1 mg); omega-3 fattyacids (including DHA) (intake per day: DHA=22.8 mg); choline (intake perday: 12 mg); phospholipids (intake per day: 12.4 mg); B vitamins (intakeper day: B6=0.1 mg; 812=0.11 μg; folic acid=18.1 ug), and antioxidants(intake per day: vitamin C=4.8 mg; vitamin E=4.5 mg; selenium=3.2 ug) orwith a control diet for 3 months. The two diets were isocaloric. Theamount of fat, carbohydrates and protein was the same between diets.During the 3 months of diet intervention, body weight was monitored aswas food intake.

Results.

Mice fed the nutritional composition showed a 25% increase in bodyweight after 3 months compared to 14% for the control mice. Food intakewas the same in the group fed the nutritional composition (on average3.10 gram per day) compared to control mice (on average 3.08 gram perday).

Conclusion.

mice showed an increase in body weight when fed with the compositionaccording to the invention (nucleoside: UMP; ω-3 polyunsaturated fattyacids (including DHA); choline; phospholipids; B vitamins, andantioxidants), not attributed to a caloric increase in body weight.

Example 5

TABLE 1 Isocaloric drink suitable for increasing BMI Component InventionAmount 125 ml Macronutrients Energy, kcal 125 Protein (caseinate/WPI), g3.8 Carbohydrate, g 16.5 Fat, g 4.9 Components according to inventioneicosapentaenoic acid. mg 300 docosahexaenoic acid, mg 1200Phospholipids, mg 106 Choline, mg 400 UMP (uridine monophosphate), mg625 Vitamin E (alpha- tocopherol 40 equivalents), mg Vitamin C, mg 80Selenium, μg 60 Vitamin B12, μg 3 Vitamin B6, mg 1 Folic acid, μg 400Minerals Sodium, mg 125 Potassium, mg 187.5 Cloride, mg 156.3 Calcium,mg 100 Phosphorus, mg 87.5 Magnesium, mg 25.0 Other trace elements Iron,mg 2 Zinc, mg 1.5 Iodine, μg 16.3 Manganese, mg 0.41 Copper, μg 225Molybdenum, μg 12.5 Chromium, μg 8.4 Other vitamins Vitamin A, μg 200Thiamin (B1), mg 0.19 Riboflavin (B2), mg 0.20 Niacin (B3), mg niacinequivalent 2.25 Pantothenic acid (B5), mg 0.66 Vitamin D, μg 0.88Biotin, μg 5.0 Vitamin K, μg 6.6

TABLE 2 Results of BMI increase (Example 5) BMI at BMI after BMI afterBaseline 3 months 6 months Invention 26.198 26.469 26.58* Control 26.17526.353 26.348 *p = 0.088

Example 6 Example Compositions According to the Invention

The following compositions according to the invention may be used forthe healthy improvement of body weight in an elderly person, inparticular a non-frail or prefrail person experiencing one or twosymptoms of frailty, preferably in elderly having a BMI of less than23.5 kg/m²:

TABLE 3 Composition A (per 100 g of ready-to-use composition) Pyrimidinenucleoside 0.3 g of a mixture of uridine and uridine monophosphateVitamin B 1 mg B6, 2 μg B12 and 300 μg folic acid or folate andoptionally one or more of: A phospholipid 0.2 g lecithin A choline 1 gcholine as choline chloride Lipids 2 g marine or algae oil, comprising30-60 g of DHA, DPA or EPA per 100 g fatty acids

TABLE 4 Composition B (sip feed, amount per 100 ml) Ingredient AmountEnergy ≧150 kcal (≧ 630 kJ) Protein ≧3.5 g Digestible carbohydrates 16 gFat 5.2 g DHA 300 mg EPA 75 mg Phospholipids 50 mg UMP 160 mg Choline100 mg Vitamin B6 0.3 mg Vitamin B12 0.8 μg Folic acid 100 mg Vitamin C20 mg Vitamin E 10 mg Selenium 15 μg Vitamin D 1.2 μg Calcium 200 mg

TABLE 5 Composition C to F Compo- Compo- Compo- Compo- sition sitionsition sition Components C D E F Macronutrients Energy (kcal) 140 100150 140 Protein (g) 8 (milk 3 (milk 10 (ultra 8 (pea protein, protein +protein) filtrated milk casein, a-lac) blend soy protein + prot/α-lac)free leucine) Lipids (EPA, DHA, 5.8 3.9 5.1 5.1 phospholipids) (g)Digestible 14 13.2 16 14 carbohydrates (g) Fiber (g) 0.2 0 0.2 0 EPA(mg) 120 240 240 200 DHA (mg) 480 960 960 800 Phospholipids (mg) 210 128128 160 Choline (mg) 200-300 320 320 260 UMP (mg) 250 500 500 400Vitamin E (mg α- 16 32 32 25 TE) Vitamin C (mg) 32 64 64 50 Selenium(μg) 67 48 48 50 Vitamin B12 (μg) 2.4 2.4 2.4 2 Vitamin B6 (mg) 0.8 0.80.8 1 Folates (μg) 320 320 320 280 Sodium (mg) 100 100 100 100 Potassium(mg) 100-200 150 100-200 100-200 Chloride (mg) 100-150 125 100-150100-150 Calcium (mg) 100-300 80 100-300 100-300 Phosphorus (mg) 100-30070 100-300 100-300 Magnesium (mg) 32 23.2 23.2 23.2 Iron (mg) 1.6 1.61.6 1.4 Zinc (mg) 2.4 1.2 1.2 2 Iodine (μg) 26 13 13 20 Manganese (mg)0.88 0.33 0.33 0.4 Copper (μg) 180 180 180 150 Molybdenum (μg) 26 10 1020 Chromium (μg) 6.7 6.7 6.7 8 Vitamin A (μg) 160 160 160 140 Thiamine(mg) 0.21 0.15 0.15 0.16 Riboflavin (mg) 0.23 0.16 0.16 0.18 Niacin (mg)2.5 1.8 1.8 2 Patothenic acid (mg) 1.4 0.53 0.53 0.6 Vitamin D (μg)  4-70.7 0.7 2 Biotin (μg) 10.5 4.0 4 6 Vitamin K (μg) 14 5.3 5.3 6

TABLE 6 Composition G: Product comprising per 1000 litres (about)Ingredient Amount (kg) Ultrafiltrated dairy protein 700 SuperrefinedTuna Fish Oil 18 Lecithin Powder 0.9 Sugar 42 Maltodextrin 118 Rapeseed-Sunflower-High Oleic Blend 32 Choline chloride 2 UMP 3.7 Potassiumhydroxide 0.27 Citric Acid Monohydraat 1.3 Magnesium hydroxide 0.6Tri-potassium citrate.1aq 0.9 Mineral Premix 0.2 Vitamin Premix 1.0Vanilla Flavour 1.2 Water added to 1000 l

Example 7 Tool for Assessing the Degree of Frailty of a Subject

Consists of answering a fixed set of questions, each related to one ormore of the aspects of frailty, and scoring the replies by comparisonwith normal values.

In order to correctly answer the questions, specific measurements arerecommended, as described in the text.

The questions can be asked by an expert and orally replied to;alternatively they can also be put on a paper or form and the replieswritten down; however, preferably the questions can be raised on ascreen or monitor of an electronic device, like a small computer, tabletor peripheral station of a central computer system.

The electronic device can have the normal values stored and can beequipped with software which allows automatic calculation of scores perparameter and of the frailty index.

The algorithm to calculate the final score can be subject to individualmedical expertise. However, it is preferred to operate with a commonalgorithm to allow comparison of diagnosis. In the text of the document,it is described how this can occur. It is preferred to score the valueof each individual parameter by comparison with age-matched controts;when the subject scores positive on two of the parameters as given belowthe subject is defined to be prefrail and can be helped by thecomposition according to the invention according the invention. When thesubject scores positive on at least three parameters, the individual isdiagnosed to be frail and to be receptive for improvement by use of thecomposition according to the invention.

TABLE 7 Example of a questionnaire for scoring frailty. Normal value/Parameter Measurements Score Muscle weakness Muscle: method: ValueExcessive feelings of Mental fatigue exhaustion or fatigue Perceivedfatigue after exercise: Activities of daily living (ADL)/sleep neededMuscle capacity or power Speed of developing fatigue Lung capacityAbnormally low Voluntary normal activities physical activityCapabilities to apply instrumental activities Slow or unsteady gait Oneor more or combinations of balance, effort (walking time) andcoordination Weight loss Average involuntary weight loss (BMI, LBM)Absence of acute weight loss or an acute phase response NeurologicalCognitive impairment dysfunction Memory disorder Sensory impairmentMotoric impairment Chronic pain Depression Sleep disorder Anxietydisorder TOTAL SCORE Prefrail: 2 Mildly frail: 3 Moderately frail: 4Severely frail: 5-6

Example: 8 Further Formulation Examples

TABLE 8 Ready to feed liquid formulations Compo- Compo- Compo- sitionsition sition Component H¹ I² J³ Volume per 125 ml 125 ml 125 m;packaging Energy 1.0 1.6 1.6 density (kcal/ml) Protein 7.5 10 8 (g/100ml) (i) Whey and (ii) Whey protein Whey protein, Ingredients/ amaranthor pea soy protein components protein (70:30) pea protein and casein(35:20:20:25 Lipids 5.1 8 8 (g/100 ml) Phospholipids = PL's 400 mgLecithin 420 mg Ingredients/ 220 mg Marine oil/corn Marine oil/soy/components Fish oil/rape seed/ oil/palm canola/lecithin lecithin 10:7:1by oil/lecithin to to get 600 mg wt, providing 600 result in 600 mg DHAand 150 mg mg DHA and 150 and 150 mg EPA EPA mg EPA Digestible 6 after9.5 11.5 Carbohydrates hydrolyses of (g/100 ml) ingredients by weight:10% galactose, 60% glucose, 10% fructose, and 10% other monosaccharidesFiber 1.5 1.5 1.5 (g/100 ml) Inuline Inuline Inuline hydrolysate +hydrolysate + hydrolysate + galacto-OS and galacto-OS and galacto-OS andmanno OS manno OS manno OS (60:20:20 by wt) (60:20:20 by wt) (60:20:20by wt) Choline 200 200 200 (mg/100 ml) Choline Choline Cholinealfosclerate alfosclerate alfosclerate Uridine source 310 320 310(mg/100 ml) Uridine + Uridine + Uridine + UMP 4:6 UMP 2:8 UMP 3:7 by wtby weight by weight Vitamins Folates: 200 ug Folates: 200 ug Folates:200 ug (amounts per B12: 6 ug B12: 6 ug B12: 6 ug 100 ml) B6: 1 mg B6: 1mg B6: 1 mg Vitamin E: 20 mg Vitamin E: 20 mg Vitamin E: 20 mg VitaminC: 40 mg Vitamin C: 40 mg Vitamin C: 40 mg Vitamin premix Vitamin premixVitamin premix providing all providing all providing all vitamins exceptvitamins except vitamins except the above in the above in the above in0.2xRDA of 0.2xRDA of 0.2xRDA of FDA 1988 FDA 1988 FDA 1988 Minerals Se:30 ug Se: 30 ug Se: 30 ug (amounts/ml) Fe: 2 mg Fe: 2 mg Fe: 2 mg Zn:1.5 mg Zn: 1.5 mg Zn: 1.5 mg Mg: 25 mg Mg: 25 mg Mg: 25 mg Ca: 120 mgCa: 120 mg Ca: 120 mg Na: 120 mg Na: 120 mg Na: 120 mg K: 180 mg K: 180mg K: 180 mg Cl: 150 mg Cl: 150 mg Cl: 150 mg P: 90 mg P: 90 mg P: 90 mgI: 16 ug I: 16 ug I: 16 ug Mn: 0.5 mg Mn: 0.5 mg Mn: 0.5 mg Cu: 0.23 mgCu: 0.23 mg Cu: 0.23 mg Mo: 13 ug Mo: 13 ug Mo: 13 ug Cr: 8 ug Cr: 8 ugCr: 8 ug ¹Product in particular suitable for increasing body mass index²Product in particular suitable for increasing lean body mass (LBM) innon-frail elderly ³Product in particular suitable for increasing ADL inpersons suffering from early physical exhaustion after exercise

Example 9 Improving BMI

Mice, 3 months of age, were provided with a diet (AIN-93) enriched witha combination of DHA+UMP (intake per day: DHA=22.8 mg; UMP=23.1 mg),B-vitamins (B6, B12 and folic acid; intake per day: B6=0.1 mg; B12=0.11ug; folic acid=18.1 ug), and phospholipids (lecithin; intake per day:12.4 mg) or with a control diet (AIN-93) for 3 months. The two dietswere isocaloric and differed only with respect to DHA, UMP, B-vitaminsand phospholipids content. The amount of fat, carbohydrates and proteinwas the same between diets. During the 3 months of diet interventionbodyweight was monitored as was food intake.

Results

Mice fed the enriched diet showed a 17.8% increase in bodyweight after 3months compared to 11.5% for the control mice. Food intake was the samein the n3PUFA+nucleotide+B-vitamins+phospholipids group (on average 3.02gram per day) compared to control mice (on average 3.08 gram per day).

Conclusion

n3PUFA+nucleotide+B-vitamins+phospholipids increases bodyweight withoutan increase in caloric intake.

Example 10 Improving BMI

Mice, 3 months of age, were provided with a diet (AIN-93) enriched witha combination of uridine-5′-monophosphate (intake per day: UMP=23.1 mg);omega-3 fatty acids (including DHA) (intake per day: DHA=22.8 mg);choline (intake per day: 12 mg); phospholipids (lecithin; intake perday: 12.4 mg); B vitamins (B6, B12 and folic acid; intake per day:B6=0.1 mg; B12=0.11 ug; folic acid=18.1 ug), and antioxidants (intakeper day: vitamin C=4.8 mg; vitamin E=4.5 mg; selenium=3.2 ug) or with acontrol diet (AIN-93) for 3 months. The two diets were isocaloric. Theamount of fat, carbohydrates and protein was the same between diets.During the 3 months of diet intervention bodyweight was monitored as wasfood intake.

Results

Mice fed the enriched diet showed a 22% increase in bodyweight after 3months compared to 11.5% for the control mice. Food intake was the samein the enriched diet group (on average 3.10 gram per day) compared tocontrol mice (on average 3.08 gram per day).

Conclusion

The combination of uridine-5′-monophosphate; omega-3 fatty acids(including DHA); choline; phospholipids; B vitamins, and antioxidantsincreases bodyweight without an increase in caloric intake.

Example 11

Tablet comprising 500 mg uridinemonophosphate, uridine or citicoline(cytidine diphosphate-choline), combined with 300 microgram sodiumfolate monglutamate and 5 microgram vitamin B12 and conventionaltabletting aids, like binders, inert filling aids, colorants, etc., toprovide a tablet of about 1 g.

The tablet is in particular suitable for increasing BMI in an elderlyperson. The skilled person will be able to provide a different dosageform providing the same or similar active ingredients in the same orother suitable dosage, based on the information disclosed herein andcommon general knowledge.

Example 12

Tablet comprising 400 mg of a nucleoside equivalent, like uridine, 6 mgvitamin B6, 200 micrrogram folate, 5 microgram vitaminB12 and 400 mg ofa choline equivalent included in conventional tabletting aids to providea tablet of about 1 g.

The tablet is in particular suitable for increasing BMI in an elderlyperson. The skilled person will be able to provide a different dosageform providing the same or similar active ingredients in the same orother suitable dosage, based on the information disclosed herein andcommon general knowledge.

Example 13

Capsule weighing about 1.9 g, comprising 700 mg marine oil, 300 mg soylecithin, 100 mg of uridine, 100 mg of UMP, 100 micogram of folate, 5 mgvitamin B6, 20 microgram vitamin B12, 10 mg vitamin E (asalpha-tocopherol) and 20 mg vitamin C, the remainder being capsulatingmaterial, e.g. gelatin,

The capsule is in particular suitable for increasing BMI in an elderlyperson. The skilled person will be able to provide a different dosageform providing the same or similar active ingredients in the same orother suitable dosage, based on the information disclosed herein andcommon general knowledge.

1. A method of increasing or maintaining body weight of a mammalcomprising administering to the mammal a composition including at leasttwo components selected from the group consisting of (i) a nucleosideequivalents, (ii) an n-3 polyunsaturated fatty acid selected from thegroup consisting of DHA, DPA and EPA, (iii) a vitamins B selected fromthe group consisting of vitamin B6, vitamin B9 and vitamin B 12 (iv) aphospholipid, (v) an antioxidants selected from the group consisting ofvitamin C, vitamin E and selenium, and (vi) a choline in a manner toincrease or maintain body weight of the mammal, with the proviso that atleast one nucleoside equivalent or at least one vitamin B is present. 2.The method of claim 1, wherein the increase or maintenance in bodyweight comprises one or more of (i) increasing or maintaining lean bodyweight and (ii) increasing or maintaining muscle mass.
 3. The method ofclaim 1, wherein the mammal is a human, and wherein body mass index isincreased or maintained.
 4. A method for improving the ability toperform an activity of daily living of a mammal, for maintaining theability to perform an activity of daily living of a mammal, or forreducing a deterioration in the ability to perform an activity of dailyliving of a mammal comprising administering to the mammal a compositionincluding at least two components selected from the group consisting of(i) a nucleoside equivalents, (ii) an n-3 polyunsaturated fatty acidsselected from the group consisting of DHA, DPA and EPA, (iii) a vitaminsB selected from the group consisting of vitamin B6, vitamin B9 andvitamin B12 (iv) a phospholipids, (v) an antioxidants selected from thegroup consisting of vitamin C, vitamin E and selenium and (vi) a cholinein a manner to improve the ability to perform an activity of dailyliving of a mammal, to maintain the ability to perform an activity ofdaily living of a mammal, or to reduce a deterioration in the ability toperform an activity of daily living of a mammal.
 5. The method of claim4, wherein the mammal is a human having a PASE-value score of 55 orless.
 6. The method of claim 1, wherein the composition includes atleast three components selected from the group consisting of (i) anucleoside equivalents, (ii) an n-3 polyunsaturated fatty acid selectedfrom the group consisting of DHA, DPA and EPA, (iii) a vitamins B, (iv)a phospholipids, (v) an antioxidants and (vi) a choline.
 7. The methodof claim 1, wherein the composition includes at least four componentsselected from the group consisting of (i) a nucleoside equivalents, (ii)a n-3 polyunsaturated fatty acids selected from the group consisting ofDHA, DPA and EPA, (iii) a vitamins B, (iv) a phospholipids, (v) anantioxidants and (vi) a choline.
 8. The method of claim 1, wherein themammal is non-frail and/or does not have dementia.
 9. The method ofclaim 1, wherein the mammal is an elderly human.
 10. The method of claim1, wherein the mammal is a human, who-when starting with the use, hashad a weight loss of 2-4.5 kg in the year preceding the start or 4-6 kgin the two years preceding the start.
 11. The method of claim 1, whereinthe nucleoside equivalent comprises a uridine source.
 12. The method ofclaim 1, wherein the phospholipid is selected from the group consistingof phosphatidylserine, phosphatidylinositol, phosphatidylcholine andphosphatidylethanolamine.
 13. The method of claim 1, wherein thecomposition is administered to the mammal as part of a nutritionalcomposition.
 14. The method of claim 1, wherein the composition isadministered to the mammal in a diet without essentially increasing thedaily caloric intake of the mammal.
 15. Nutritional composition,comprising i) uridine and/or uridine monophosphate ii) DHA and EPA iii)a vitamin B selected from the group consisting of vitamin B6, vitamin B9and vitamin B12 iv) a phospholipid v) an antioxidant selected from thegroup consisting of vitamin C, vitamin E and selenium vi) a choline vii)a protein, wherein the composition comprises phosphatidylcholine, andthe weight to weight ratio phosphatidylcholine to choline is more than0.26.
 16. Nutritional composition according to claim 15, wherein theweight to weight ratio urdine to uridine monophosphate is in the rangeof 0.2:1 to 0.7:1.
 17. Nutritional composition according to claim 15,wherein the total content of uridine plus uridine monophosphate is inthe range of 5-30 mg per gram dry weight.
 18. Nutritional compositionaccording to claim 15, comprising 5-10 mg EPA per gram dry weight and2.5-20 mg DHA per gram dry weight.
 19. Nutritional composition accordingto claim 15, wherein, the protein content is less than 400 mg per gramdry matter.
 20. Nutritional composition according to claim 15, having anenergy density of less than 13 kcal per gram dry matter.
 21. Nutritionalcomposition according to claim 15, wherein the phospholipid content isin the range of 3.3-67 mg/gram dry matter.
 22. Nutritional compositionaccording to claim 15, wherein the weight ratio phosphatidylcholine tocholine is 0.26-6.
 23. Nutritional composition according to claim 15,wherein the composition comprises (iii) vitamin B6, vitamin B12 andvitamin B9, (v) vitamin C, vitamin E and selenium and (vi) at least onecholine selected from the group consisting of choline chloride andcholine alfosclerate.
 24. Nutritional composition according to claim 15,wherein the composition comprises at least two different phospholipidsselected from the group consisting of phosphatidylserine,phosphatidylinositol, phosphatidylcholine and phosphatidylethanolamine.25. Nutritional composition according to claim 15, wherein the ratio[uridine monophosphate+uridine]/[phospholipds] is less than 5.9. 26.Nutritional composition according to claim 15, wherein the nutritionalcomposition comprises at least a whey protein.
 27. Nutritionalcomposition according to claim 15, comprising a protein selected fromthe group consisting of fish proteins, egg-protein and vegetableproteins.
 28. Nutritional composition according to claim 27, comprisinga vegetable protein selected from the group consisting of potatoprotein, soy protein, pea protein, beans protein, lupin protein, quinoaprotein and amaranth protein.
 29. Nutritional composition according toclaim 15, comprising one or more proteins, wherein the total content ofnon-dairy protein is more than 21 wt. %.
 30. Nutritional compositionaccording to claim 15, comprising 0.15-0.5 g digestible carbohydrate pergram dry weight.
 31. Nutritional composition according to claim 15,comprising 0.15-0.3 g lipids per gram dry weight.
 32. Nutritionalcomposition according to claim 15, wherein the composition is a liquid.33. Nutritional composition according to claim 32, having a dry mattercontent of 15-30 g per 100 ml.
 34. Nutritional composition according toclaim 32 having an osmolarity of less than 450 mEq/l.
 35. Nutritionalcomposition according to claim 15, wherein the composition is a powder.